Cognitive Enhancers (Nootropics). Part 2: Drugs...

Journal of Alzheimer’s Disease 42 (2014) 1–68DOI 10.3233/JAD-140402IOS Press

1

Review

Cognitive Enhancers (Nootropics). Part 2:Drugs Interacting with Enzymes. Update2014

Wolfgang Froestl∗, Andreas Muhs and Andrea PfeiferAC Immune SA, EPFL, Lausanne, Switzerland

Accepted 25 March 2014

Abstract. Scientists working in the field of Alzheimer’s disease and, in particular, cognitive enhancers are very productive. Thereview on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potentialtargets for the treatment of Alzheimer’s disease were identified. This update describes drugs interacting with 60 enzymes versus43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. Thepresent review covers the evolution of research in this field through April 2014.

Keywords: Alzheimer’s disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine

1. INTRODUCTION

As of May 2, 2014, there are 28,230 entries inPubMed under the term cognitive enhancers, 28,255entries under the term nootropic, and 313 entriesunder the term cognition enhancers. Scifinder lists5,698 references under the research topic nootropic,655 references under the term cognitive enhancer,and 11,248 references for cognition enhancers. TheThomson Reuters Pharma database lists 1,249 drugsas nootropic agents or cognition enhancers and giveszero results under the term cognitive enhancer. Theterm nootropics was coined by the father of piracetamCorneliu Giurgea in 1972/1973 [1, 2] NOOS = mindand TROPEIN = toward.

Nootropics are drugs to treat cognition deficits,which are most commonly found in patients sufferingfrom Alzheimer’s disease (AD), schizophrenia, stroke,attention deficit hyperactivity disorder (ADHD), or

∗Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,EPFL, Innovation Park, Building B, CH-1015 Lausanne, Switzer-land. Tel.: +41 21 693 91 43; Fax: +41 21 693 91 20; E-mail:[email protected].

aging. Mark J. Millan and 24 eminent researchers[3] presented an excellent overview on cognitivedysfunction in psychiatric disorders in the Febru-ary 2012 issue of Nature Reviews Drug Discoveryand defined cognition as “a suite of interrelated con-scious (and unconscious) mental activities, includingpre-attentional sensory gating, attention, learning andmemory, problem solving, planning, reasoning andjudgment, understanding, knowing and representing,creativity, intuition and insight, spontaneous thought,introspection, as well as mental time travel, self- aware-ness and meta cognition (thinking and knowledgeabout cognition)”.

Since a first review in 1989 on “Families of Cogni-tion Enhancers” by Froestl and Maitre [4], substantialprogress has been made in the understanding ofthe mechanism(s) of cognitive enhancers. Therefore,we propose a new classification to assign cognitionenhancing drugs to 19 categories:

1. Drugs interacting with Receptors (Part 1)2. Drugs interacting with Enzymes (Part 2)3. Drugs interacting with Cytokines (Part 3)

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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2 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

4. Drugs interacting with Gene Expression (Part3)

5. Drugs interacting with Heat Shock Proteins(Part 3)

6. Drugs interacting with Hormones (Part 3)7. Drugs interacting with Ion Channels

( /= Receptors) (Part 3)8. Drugs interacting with Nerve Growth Factors

(Part 3)9. Drugs interacting with Re-uptake Transporters

(Part 3)10. Drugs interacting with Transcription Factors

(Part 3)11. Antioxidants (Part 3)12. Metal Chelators (Part 3)13. Natural Products (Part 3)14. Nootropics (“Drugs without mechanism”)

(Part 3)15. Peptides (Part 3)16. Drugs preventing amyloid-� aggregation (Part

3)16.1 Ligands interacting with amyloid-� (Part 3)16.2 Inhibitors of serum amyloid P component

binding (Part 3)16.3 Vaccines against amyloid-� (Part 3)16.4 Antibodies against amyloid-� (Part 3)17. Drugs interacting with tau, prion, �-synuclein,

ApoE, and TDP-43(Part 3)17.1 Drugs preventing tau, prion or �-synuclein

aggregation (Part 3)17.2 Ligands interacting with tau and �-synuclein

(Part 3)17.3 Vaccines against tau and �-synuclein (Part 3)17.4 Antibodies against tau, superoxide dismutase

1, �-synuclein, and ApoE (Part 3)18. Stem Cells (Part 3)19. Miscellaneous (Part 3)

In Part 1, drugs interacting with receptors weredescribed [5]. In Part 2, we described drugs interactingwith enzymes [6] and in Part 3, drugs interacting withtargets 3 to 10 and compounds and preparations of cate-gories 11 to 19 [7]. However, this field is very dynamic.New potential potential targets were identified. Somecompounds progressed in their development, whilemany others were discontinued. Therefore an updateis appropriate.

2. DRUGS INTERACTING WITH ENZYMES

Researchers have been investigating drugs inter-acting with a wide variety of enzymes in order to

identify valuable cognition enhancers. These enzymesare:

2.1. Drugs interacting with acetyl- and butyryl-cholinesterase (AChE & BChE)

2.1.1. Drugs inhibiting AChE and other biologi-cal targets

2.1.1.1. Dual AChE inhibitors and AChE receptorligands

2.1.1.2. Dual AChE and amyloid-� inhibitors2.1.1.3. Dual AChE inhibitors and antioxidants2.1.1.4. Dual AChE and �-secretase-1 or

�-secretase inhibitors2.1.1.5. Dual AChE inhibitors and calcium channel

blockers2.1.1.6. Dual AChE inhibitors and cannabinoid

receptor antagonists2.1.1.7. Dual AChE and fatty acid amide hydrolase

inhibitors2.1.1.8. Dual AChE inhibitors and histamine H3

receptor antagonists2.1.1.9. Dual AChE and monoamine oxidase

inhibitors2.1.1.10. Dual AChE inhibitors and metal

chelators2.1.1.11. Dual AChE inhibitors and N-methyl-D-

aspartic acid receptor channel blockers2.1.1.11.1. Dual AChE inhibitors and platelet activat-

ing factor antagonists2.1.1.12. Dual AChE and serotonin transporter

inhibitors2.1.1.13. Dual AChE and sigma receptor inhibitors

2.2. Drugs interacting with acetyltransferases2.3. Drugs interacting with �-Secretase2.4. Drugs interacting with �-Secretase2.5. Drugs interacting with �-Secretase

2.5.1. �-Secretase Inhibitors2.5.2. �-Secretase Modulators2.5.3. Inhibitors of �-Secretase Activating

Protein2.5.4. Notch Pathway Inhibitors

2.6. Drugs interacting with Aminoacylase 32.7. Drugs interacting with Amyloid Binding

Alcohol Dehydrogenase2.8. Drugs interacting with Angiotensin Con-

verting Enzyme (ACE)2.9. Drugs interacting with �-Hexosaminidase

2.10. Drugs interacting with 11�-Hydroxysteroid Dehydrogenase

2.11. Drugs interacting with Calpain2.12. Drugs interacting with Carbonic Anhy-

drase

W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014 3

2.13. Drugs interacting with Carnitine Acetyl-transferase

2.14. Drugs interacting with Caspases2.15. Drugs interacting with Catechol-O-

methyltransferase2.16. Drugs interacting with Cathepsin2.17. Drugs interacting with Cholesterol 24S-

Hydroxylase (CYP46A1)2.18. Drugs interacting with Cyclooxygenase

(COX)2.19. Drugs interacting with Cytochrome P450

(CYP) isoforms ( /= CYP46A1)2.20. Drugs interacting with D-Amino Acid Oxi-

dase2.21. Drugs interacting with Dipeptidyl-

peptidase2.22. Drugs interacting with Glutaminyl Cyclase2.23. Drugs interacting with Glyceraldehyde-3-

Phosphate Dehydrogenase2.24. Drugs interacting with Glycogen Synthase

Kinase-3� (GSK-3�)2.25. Drugs interacting with Guanylyl Cyclase2.26. Drugs interacting with Heme Oxgenase2.27. Drugs interacting with Histone Deacety-

lases ( /= Sirtuins)2.28. Drugs interacting with HMG-CoA Reduc-

tase2.29. Drugs interacting with Insulin-Degrading

Enzyme2.30. Drugs interacting with Insulin-Regulated

Aminopeptidase2.31. Drugs interacting with Kinases ( /= GSK-

3� and /= PKC)2.32. Drugs interacting with Kynurenine Mono-

Oxygenase and Kynurenine TransaminaseII

2.33. Drugs interacting with 5-Lipoxygenase2.34. Drugs interacting with Lysine Specific His-

tone Demethylase 12.35. Drugs interacting with Monoacylglycerol

Lipase2.36. Drugs interacting with Monoamine Oxi-

dase2.37. Drugs interacting with Myeloperoxidase2.38. Drugs interacting with Neprilysin2.39. Drugs modulating O-linked

N-Acetylglucosaminidase2.40. Drugs interacting with Peptidyl-Prolyl cis-

trans Isomerase D2.41. Drugs interacting with Phosphodiesterases2.42. Drugs interacting with Phospholipases A2

and D2

2.43. Drugs interacting with Plasminogen Acti-vator Inhibitor

2.44. Drugs interacting with Poly ADP-RibosePolymerase

2.45. Drugs interacting with human PresequenceProtease

2.46. Drugs interacting with Prolyl Endo Pepti-dase

2.47. Drugs interacting with Prostaglandin D &E Synthases

2.48. Drugs interacting with Protein Kinase C(PKC)

2.49. Drugs interacting with Protein Phos-phatase Slingshot Homolog 2

2.50. Drugs interacting with Protein TyrosinePhosphatase

2.51. Drugs interacting with Rac1 GTPase2.52. Drugs interacting with Ras Farnesyl Trans-

ferase2.53. Drugs interacting with Rho GTPase2.54. Drugs interacting with

S-Adenosylhomocysteine Hydrolase2.55. Drugs interacting with Serine Palmitoyl-

transferase2.56. Drugs interacting with Sirtuin2.57. Drugs interacting with Steroid Sulfatase2.58. Drugs interacting with Synaptojanin 12.59. Drugs interacting with Transglutaminase2.60. Drugs interacting with Ubiquitin

Carboxyl-terminal Hydroxylase (Usp14).

2.1. Drugs interacting with acetyl- andbutyrylcholinesterase

Since the publication of the cholinergic hypoth-esis of AD by Bartus and colleagues in 1982 [8],tremendous efforts have been undertaken to find eitherselective acetylcholine receptor agonists (described inPart 1) or acetylcholinesterase (AChE) inhibitors. Inretrospect, the latter approach (i.e., AChE inhibitors)turned out to be more successful than the big effortsto find selective acetylcholine receptor agonists. Forreviews on cholinesterase inhibitors for AD, see [9,10]. Interestingly, APOE and BChE were identifiedas modulators of cerebral amyloid-� deposition in agenome-wide association study (GWAS) [723].

Donepezil (Aricept; E2020; co-developed by Eisai,Tokyo and Pfizer, Fig. 1) was approved by the FDAin November 1996 and was launched in the US inJanuary 1997 for the treatment of mild to moder-ate AD. In October 2006, FDA approval for thetreatment of severe AD was granted. It potently


Fig. 1. Launched acetylcholinesterase inhibitors.

blocked AChE (IC50 = 23 nM), whereas blockadeof Butyrylcholinesterase (BChE) was 320 timesweaker (IC50 = 7′420 nM) [11]. The Japanese inven-tors disclosed values of IC50 = 5.7 nM for AChEand IC50 = 7′140 nM for BChE (factor 1250) [12].Donepezil interacts with the active site of AChE andthe peripheral anionic site of the enzyme [13]. Itslong terminal disposition half-life of 70 hours supportsonce-daily administration [14].

The sales for donepezil reported by Eisai for 2012were USD 1.178 billion (Thomson Reuters Pharma,update of May 6, 2014).

There are currently 2,635 publications on donepezillisted in PubMed (as of May 2, 2014).

A 10-year perspective on donepezil was presented[15]. Two meta-analyses of the efficacy of donepezil,rivastigmine, galantamine, and memantine for thetreatment of AD were published [16, 17]. Broaderconsiderations of higher doses of donepezil in thetreatment of mild, moderate, and severe AD were com-municated [18], in particular on the question of the caseof the 23 mg dose [19, 20]. For the effects of donepezilon levels of cholinesterases in the cerebrospinal fluid(CSF) of AD patients, see [21]. Donepezil combinedwith natural hirudin improved the clinical symptomsof patients with mild-to-moderate AD [22].

A combination treatment of donepezil and meman-tine showed beneficial effects in AD patients inreducing cognitive worsening [23, 24].

Donepezil was used for the treatment of patientswith Parkinson’s disease (PD) [25] and for the treat-ment of memory impairment in multiple sclerosis (MS)patients [26].

NAL-8812 is a 3-day patch formulation co-developed with NAL Pharmaceuticals (Hong Kong)since November 2012 (Thomson Reuters Pharma,update of January 17, 2014). The Immediate Suspen-sion (ImSus) encapsulation by ALRISE Biosystems(Berlin) is in preclinical evaluation (Thomson ReutersPharma, update of May 27, 2014).

NAL-8817 is an orally dissolving film formulationof donepezil using the BIO-FX fast-onset oral cavitydrug delivery system technology (Thomson ReutersPharma, update of January 17, 2014).

Deuterated donepezil (DeuteRx, a spun-off fromDeuteria Pharmaceuticals, Andover, MA) is investi-gated for the potential treatment of AD (ThomsonReuters Pharma, update of March 17, 2014).

Donepezil + memantine (ADS-8704, MDX-8704;Arimenda; Namenda XR; Adamas Pharmaceuticals,Emeryville, CA in collaboration with Forest Labora-tories, New York), a once-daily fixed dose combinationextended release formulation, is currently tested inPhase III clinical trials in the US and in EU. Firstclinical results were presented [27]. US NDA filingis planned for 2014 and launch is expected in 2015(Thomson Reuters Pharma, update of February 4,2014).

ANAVEX PLUS (Anavex Life Sciences, Vancou-ver, BC) is a combination of the sigma-1 receptoragonist Anavex-2-73 and donepezil for the potentialtreatment of AD. In January 2014, clinical develop-ment with the Roskamp Institute (Sarasota, FL) wasplanned (Thomson Reuters Pharma, update of April23, 2014).

Rivastigmine (Exelon, SDZ-ENA-713; SDZ-212-713; ENA-713; Novartis, Fig. 1) is a potent BChEinhibitor (IC50 = 37 nM). It blocks AChE with anIC50 = 4,150 nM, a factor of 112 times less than BChE[11]. It forms a carbamoylated complex with the active-site serine inactivating it for about 10 hours producinga “pseudo-irreversible” inhibition. Rivastigmine waslaunched for the treatment of mild to moderate AD in2000 in EU and the US and in 2010 in Japan. It wasapproved for the treatment of mild to moderately severedementia associated with idiopathic PD. Rivastigminetransdermal patch was launched in EU in 2007 andin Japan in 2011 in collaboration with the Japaneselicensee Ono Pharmaceuticals.

Sales for rivastigmine for 2013 by Novartis wereUSD 1.032 billion; sales by Ono for 2012 were USD48.8 million (Thomson Reuters Pharma, update of June3, 2014).

There are currently 1,341 publications on rivastig-mine listed in PubMed (as of May 2, 2014).


Rivastigmine was evaluated for the treatment ofdementia in PD [28]. Rivastigmine was also effectivein patients with dementia with Lewy bodies. Bene-fits were seen on tests of attention, working memory,and episodic secondary memory [29]. Rivastigminewas successfully applied for the treatment of vascu-lar dementia [30–33], for treatment of hallucinationsin Creutzfeldt-Jakob disease [34], and memory deficitsinduced by electroconvulsive therapy [35].

Many reviews exist on results of clinical trialsusing the rivastigmine transdermal patch describ-ing enhanced tolerability and significantly less sideeffects. A 24 week, randomized, controlled trial ofrivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 hdemonstrated superior efficacy of the 13.3 mg/24 hpatch over the 4.6 mg/24 h patch on the Severe Impair-ment Battery and the AD Cooperative Study–Activitiesof Daily Living scale–Severe Impairment Version [36,37] (Thomson Reuters Pharma, update of June 9,2014).

Rivastigmine transdermal patch formulation(Samyang, Seoul) is in Phase I clinical evaluation sinceNovember 2013 (Thomson Reuters Pharma, update ofJanuary 7, 2014).

Rivastigmine transfilm is a sustained releasetransdermal patch formulation of Tesa Labtech(Langenfeld, Germany) in preclinical development(Thomson Reuters Pharma, update of January 7, 2014).

Galantamine (Razadyne, Reminyl, Nivalin;Janssen Pharmaceutica, Beerse, BE, part of Johnson& Johnson, Shire and Takeda under license fromSanochemia; Fig. 1) is an alkaloid extracted fromthe bulbs of the Amaryllidaceae family that includedaffodils and the common snowdrop (Galantheaworonowii [38]). It blocks AChE (E.C. 3.1.1.7) withan IC50 of 800 nM and BChE (E.C. 3.1.1.8) with anIC50 of 7,320 nM [11]. Galantamine was launched in2001 for the treatment of mild to moderate AD in EUand the US and in March 2011 in Japan.

The sales of galantamine in 2011 for Johnson &Johnson were USD 470 million, for Shire in 2012 USD38 million and for Takeda in 2012 USD 105 million(Thomson Reuters Pharma, update of May 6, 2014).

There are currently 1,786 publications on galan-tamine (or galanthamine) listed in PubMed (as of May2, 2014).

A commercial scale process of galantamine hydro-bromide was presented by chemists of AurobindoPharma [39, 40].

The binding interactions of galantamine withamyloid-� (A�) peptide were elucidated [41]. Galan-tamine not only blocks AChE and BChE, but also

acts as a positive allosteric modulator of nicotinicacetylcholine receptors enhancing the concentrationsof acetylcholine in the brain by a second mechanism[42].

Long-term effects of galantamine treatment on brainfunctional activities were measured by positron emis-sion tomography (PET) in AD patients [43]. Forgalantamine in PD, see [44]; in schizophrenic patients[45]; in vascular dementia [46].

Johnson & Johnson (New Brunswick, NJ) and Shire(Basingstoke, UK) under the license of Synaptec(Spokane, WA) developed and launched Razadyne ER(Reminyl XL), an extended release capsule formula-tion, in April 2005 in the US [47, 48] (Thomson ReutersPharma, update of June 3, 2014).

NAL-8801 (NAL Pharmaceuticals, Hong Kong) isa one day patch formulation of galantamine using theBio-D3 transdermal drug delivery system technologyin preclinical evaluation (Thomson Reuters Pharma,update of January 17, 2014).

Memogain (GLN-1062; Neurodyn, Charlottetown,Canada under license from Galantos Pharma; Heidel-berg) is a prodrug, the benzoyl ester, of galantamineadministered as an intranasal formulation [49]. InDecember 2013, the 2-part, single ascending dosePhase Ia trial was initiated in the Netherlands. InJanuary 2014, the double-blind, placebo-controlled,two single ascending dose (5.5 and 11 mg) was com-pleted in healthy young subjects (n = 16). Interim datareported that the drug was safe and well toleratedand significantly enhanced working memory in thehealthy subjects (Thomson Reuters Pharma, update ofFebruary 25, 2014).

Huperzine A (Cerebra; Shanghai Institute of Mate-ria Medica; Fig. 1) is a natural Lycopodium alkaloidfound in extracts from Huperzia serrate [50]. It waslaunched in China for the treatment of AD in 1995.The drug is administered in low oral doses of 0.1 mgfour times a day. Its pharmacology, efficacy and safetywas extensively described [724–728]. See also Part 3,Chapter 13. Natural products.

A large-scale synthesis resulted from a joint ventureby process chemists of Shasun Pharma (UK and India),Rhodia Pharma (USA), and Debiopharm (Switzerland)[51]. Shasun Pharmaceuticals and Debiopharm enteredinto a licensing agreement for the manufacturing andcommercialization of Huperzine A (Thomson ReutersPharma, update of August 29, 2013).

There are currently 455 publications on huperzineA listed in PubMed (as of May 27, 2014).

The mechanism of Huperzine A seems to play viaWnt/�-catenin signaling [52]. Chronic administration


Fig. 2. Acetylcholinesterase inhibitors in development or in preclinical evaluation.

of huperzine A to double transgenic mice led to anincrease in ADAM10 and a decrease in �-secretase-1(BACE1) and amyloid-� protein precursor (A�PP)695protein levels. Huperzine A was also evaluated intriple transgenic mice confirming the improvement ofcognitive performance and the non-amyloid pathwayactivation [53]. Huperzine A reduced iron levels inbrains of AD mice [54].

XEL-001HP (Xel Pharmaceuticals, Draper, UT incollaboration with Guangzhou Xiangxue Pharmaceu-tical, Guandong) is a once-weekly sustained releasetransdermal patch formulation. This formulation wastested in a Phase I clinical trial in China starting inSeptember 2008. The drug is in Phase II trials in Chinasince March 2011 (Thomson Reuters Pharma, updateof December 31, 2013).

XEL-001HG (Xel Pharmaceuticals, Draper, UT) isa sustained release topical gel formulation in preclin-ical evaluation (Thomson Reuters Pharma, update ofJanuary 3, 2014).

Posiphen (the (+)-enantiomer of phenserine, QRPharma, Berwyn, PA under license from TorreyPinesTherapeutics, La Jolla, CA, Fig. 2) is in Phase II clin-ical trials for the oral treatment of AD since June2009. Posiphen also blocked the expression of brain

�-synuclein [55, 56]. Posiphen is a candidate drug tolower CSF A�PP, A� peptide, and tau levels in humans[57]. The synthesis of its primary metabolic productswas described [58]. For its neurotrophic actions, see[59] (Thomson Reuters Pharma, update of December23, 2013).

Shen Er Yang (Changchun Huayang High Technol-ogy Co Ltd., Shanghai, Fig. 2) is a tablet formulation of1,2,3,4,5,6,7,8-octohydro-9-aminoacridine succinate,a dual cholinesterase inhibitor in Phase II clinicaltrials since March 2011. A single-center, random-ized, open-label, dose-escalation study to evaluatethe pharmacokinetics in healthy Chinese subjects wasdescribed [60] (Thomson Reuters Pharma, update ofSeptember 11, 2013).

Bisnorcymserine (QR Pharma, Radnor, PA underlicense from TorreyPines Therapeutics, La Jolla CA;Fig. 2) is a dual BChE and A�PP inhibitor. In June2012 a Phase I, single-ascending-dose, safety studywas planned in elderly volunteers (expected n = 72). InJuly 2012, the trial was initiated and was to be con-ducted by the NIA/NIH clinical research group underan NIH clinical trial agreement. In November 2012, asecond Phase I trial was initiated (Thomson ReutersPharma, update of April 26, 2013).


Fig. 3. Acetylcholinesterase inhibitors in preclinical evaluation II.

There are several cholinesterase inhibitors in pre-clinical evaluation (in alphabetical order):

FS-0311 (Shanghai Institute for Materia Medica;Fig. 2) is a bis-huperzine B derivative with similarpotency for the inhibition of AChE as donepezil buthigher potency than huperzines A and B. It antago-nized cognitive deficits induced by scopolamine or bytransient brain ischemia [61].

The most potent AChE inhibitor is the moleculesyn-1 (Fig. 3) with Kd of 77 fM synthesized at theScripps Research Institute (La Jolla, CA) linking atacrine part via click chemistry to a phenanthridiumunit. The tacrine part is binding to the catalytic site,the phenanthridium piece is located at the peripheralsite of AChE [62].

The University of Nebraska Medical Center(UNMC, Omaha, NE) investigates an 18F labeled 2′-deoxy-3′-fluorothymidine derivative (Fig. 3), whichbinds irreversibly and inhibits BChE and may be usefulas a diagnostic agent for imaging of AD [63] (ThomsonReuters Pharma, update of April 3, 2013).

Many new scaffolds for AChE inhibitors werediscovered recently, such as isoxazoles [64],quinolino-donepezils [65], new semicarbazones of4-aminopyridine and 7-methoxytacrine-adamanty-lamine heterodimers [66–68] and phenylcinnamidederivatives [729]. 1,2,3,4-Tetrahydrobenzo[h] [1,6]naphthyridines were described as potent peripheral-to-midgorge-site inhibitors of AChE [69]. Foralkaloids as a source of potential AChE inhibitors, see[70].

Excellent reviews describe novel virtual screeningtechniques [71, 72].

The development of many AChE inhibitors wasterminated (in alphabetical order): of bis-(7)-tacrine(Mayo Foundation; [73]), huprines (UniversitatAutonoma de Barcelona [74–88], methanesulfonylfluoride (SNX-001; SeneXta; [89–95]), NP-0336(Noscira), (−)-phenserine (Axonyx under licensefrom NIH and Daewoong Pharmaceuticals; [96–99];it was proposed to retest (−)-phenserine by avoid-ing methodological deficiences of the first clinicaltrial; [100]), protexia (PEGylated recombinant humanbutyryl-cholinesterase; PharmAthene under licensefrom Nexia Biotechnologies; [101, 102]), SPH-1285and SPH-1359 (Sanochemia) and of WIN-026 (INM-176, KR-WAP-026; WhanIn, Seoul under license fromScigenic & Scigen Harvest; [103, 104]).

2.1.1. Drugs inhibiting AChE and otherbiological targets

Tremendous efforts have been undertaken to com-bine AChE inhibition and interaction with multipletargets thought to be responsible for AD pathogenesisto create “multi-target-directed ligands” [105, 106].

2.1.1.1. Dual AChE inhibitors and AChE receptorligands. The development of MHP-133 (an AChEinhibitor interacting with M1 muscarinic acetyl-choline, 5-HT4 and I2 imidazoline receptors, MedicalCollege of Georgia; [107, 108]) and of Ro-46-5934 (adual AChE inhibitor and M2 AChR antagonist, Roche;[109]) was discontinued.

2.1.1.2. Dual AChE and amyloid-� inhibitors. AChEcolocalizes with A� peptide deposits in the brains of


Fig. 4. Dual acetylcholinesterase and amyloid-� inhibitors.

AD patients and promoted A� fibrillogenesis by form-ing stable AChE-A� complexes. A new motif in theN-terminal of AChE triggers A� aggregation and depo-sition [110].

AVCRI-104P (University of Barcelona and Fun-dacio Bosch I Gimpera, Fig. 4) is a multifunctionaltherapeutic that inhibited A� aggregation includingAChE- and self-induced A� aggregation, BACE1 andAChE and BChE for the potential treatment of AD(Thomson Reuters Pharma, update of April 10, 2014).

Meserine (Shanghai Jiao Tong University Schoolof Medicine, Fig. 4) is a potent AChE inhibitor(IC50 = 274 nM) lowering A�42 levels by 42% inA�PP/PS1 transgenic mice cerebrum after i.p. injec-tion of 7.5 mg/kg [111].

This is an area of research with numerous novelcontributions presenting O-hydroxyl-or O-aminoben-zylamine-tacrine hybrids [112], phenylthiazole-tacrinehybrids [113], benzo[e][1, 2, 4]triazin-7(1H)-one and[1, 2, 4]-triazino[5,6-jk]carbazol-6-one derivatives[114] and N’-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives [115]. Thioflavin- anddeferiprone-based molecules acted as AChEinhibitors and dissociated toxic A� aggregates[116]. Sym-triazines and 1,4-substituted 4-(1H)-pyridylene-hydrazones inhibited A� fibril formationand AChE [117–119], as did tacrine-benzothiazolehybrids [120] and novel tacrine analogs [121, 122].Rhein–huprine hybrids showed AChE and BChEinhibiting properties and BACE1, dual A�42, andtau anti-aggregating activities [123]. Genistein-O-alkylbenzylamines showed good AChE inhibitoryactivity and significant inhibition of A� aggregation[124]. D-ring opened galantamine analogues showedpotent inhibition of AChE and good A�42 aggregationinhibitory activity [125]. A ruthenium (II) polypyridylcomplex showed AChE and A� aggregation inhibitingproperties [126]. Benzylisoquinoline derivativesshowed strong AChE inhibitory activity and inhibitedself-induced A� aggregation [730].

The development of NP-61 (NP-0361; Noscira, pre-viously Neuropharma; [127, 128]) was terminated.

2.1.1.3. Dual AChE inhibitors and antioxidants.Several dual-acting drugs with potent AChE inhibit-ing activity and antioxidant properties were presented,such as novel 4-dimethylamine flavonoid derivatives,which exhibited high AChE and BChE inhibitoryactivity and showed potent oxygen radical absorbancecapacity [129]. 3,4-dihydroxybenzoic acid deriva-tives acted as antioxidants and AChE inhibitors[130]. Fused donepezil and ebselen derivatives weredescribed [131, 132], as were chromenotacrines [133],novel tacrine-carbazole hybrids [134], quinolone-benzylpiperidine derivatives [135], melatonin-N,N-dibenzyl(N-methyl)amine hybrids [136] and 1H-phenanthro[9,10-d]imidazoles [731].

2.1.1.4. Dual AChE and �-secretase-1 or �-secretaseinhibitors. Tacrine-flurbiprofen hybrids showedsuperior AChE inhibitory activities [137, 138]. Othertacrine-flurbiprofen hybrid compounds acted as poten-tial BChE inhibitors with vasorelaxation activity[139].

2.1.1.5. Dual AChE inhibitors and calcium channelblockers. The development of bis(7)-tacrine (MayoFoundation; [73]) was terminated.

2.1.1.6. Dual AChE inhibitors and cannabinoid recep-tor antagonists. Novel CB2 cannabinoid agonists withadditional BChE inhibiting properties were disclosed[140].

The development of Compound 20 (Solvay, nowAbbVie, North Chicago, IL) was terminated [141].

2.1.1.7. Dual AChE & fatty acid amide hydrolaseinhibitors. MIQ-001 (Meta-IQ Aps, Aarhus, Den-mark) is a fatty acid metabolism inhibitor for thepotential treatment of AD. A Phase I healthy volun-teer study was performed starting in February 2010(Thomson Reuters Pharma, update of May 3, 2013).The structure was not communicated.

2.1.1.8. Dual AChE inhibitors and histamine H3receptor antagonists. A computational analysis of


Fig. 5. Two dual acetylcholinesterase and MAO and an ATase1/2inhibitor(s).

novel drugs designed for use as AChE inhibitorsand histamine H3 receptor antagonists for AD wasdescribed [142].

2.1.1.9. Dual AChE and monoamine oxidaseinhibitors. Ladostigil (TV-3326; Avraham Pharma-ceuticals, Yavne, Israel under license from YissumResearch Development, a wholly owned companyof the Hebrew University of Jerusalem; Fig. 5)combines the carbamate moiety of the BChE inhibitorrivastigmine with the propargylamine pharmacophoreof the MAO-B inhibitors selegiline and rasagiline.Ladostigil is currently in Phase IIb clinical trials in190 patients in Europe since December 2010 for theoral treatment of AD. In February 2012 a Phase II trialwas initiated in Israel and Europe in patients sufferingfrom mild cognitive impairment (MCI) (ThomsonReuters Pharma, update of August 29, 2013). Seealso section 2.36. Drugs interacting with MonoamineOxidase.

Spanish and Italian medicinal chemists describedpotent dual cholinesterase and MAO inhibitors[143–145]. One example is ASS234 (UniversitatAutonoma de Barcelona and CSIC, Madrid; Fig. 5),which is also an antioxidant, inhibited A� aggrega-tion and protected from A�-induced apoptosis in vitro(Thomson Reuters Pharma, update of July 22, 2013).

2.1.1.10. Dual AChE inhibitors and metal chelators. Areview described the field in great detail [146]. Novelbis-(-)-normeptazinol derivatives act as dual bindingsite AChE inhibitors with metal-complexing properties[147, 148].

2.1.1.11. Dual AChE inhibitors and NMDA recep-tor channel blockers. Novel data were presented in

the review “rationally designed multi-targeted agentsagainst neurodegenerative diseases” [149].

2.2. Drugs interacting with acetyltransferases

Scientists of the University of Wisconsin (Madison,WI) investigated acetyl-CoA:lysine acetyltransferase(ATase1/2) inhibitors such as Compound 9 (Fig. 5)for the potential prevention and treatment of AD [150].ATase1/2 inhibitors reduced BACE1 and A� levels inan A�PP695/swe mouse model of AD. One compounddecreased BACE1 and A� levels and prevented synap-tic and cognitive defects (Thomson Reuters Pharma,update of November 27, 2013).

2.3. Drugs interacting with alpha-secretase

�-secretase cleaves A�PP at the Lys16-Leu17 bondwithin the A� sequence to generate the solubleN-terminal A�PP fragment (sA�PP�) and the mem-brane bound CTF83 (carboxy-terminal fragment of 83residues in length) thus precluding the formation andsubsequent deposition of A�.

Bryostatin-1 (Neurotrope BioScience, Plantation,FL in collaboration with the Blanchette RockefellerNeurosciences Institute, Morgantown, WV) is a nat-urally occurring PKC activator isolated from theCalifornian marine bryozoan Bugula neritina. In April2014 the program was listed as being in Phase IIadevelopment for familial AD, clinical developmentfor fragile X syndrome, and in lead optimization forischemic stroke and traumatic brain injury. Bryostatin-1 improved survival and reduced ischemic brain injuryin aged rats after acute ischemic stroke [151] (Thom-son Reuters Pharma, update of June 5, 2014). See alsoChapter 2.48. Drugs interacting with Protein Kinase C.

APH-1104 (Amylon LLC, a spin-off of Aphios,Woburn, MA) is a potent �-secretase modulator forthe potential oral treatment of mild to moderate AD,cognitive disorders, and other CNS disorders includingDown’s syndrome and glaucoma. In November 2013,preclinical data were reported. It is more potent than thePKC modulator APH-0703 (see Chapter 2.48; Thom-son Reuters Pharma, update of November 21, 2013).The structure was not communicated.

DIA-10-D (Arizona State University, Tempe, AZand the Roskamp Institute, Sarasota, FL) is a bispe-cific tandem single chain (scFv) antibody combiningiBSEC1 with the ASec1A, which simultaneouslyinhibited BACE and promoted �-secretase processingof A�PP. The iBSEC1 scFv was selected, since it rec-ognizes the BACE1 cleavage site on A�PP but does


not bind the adjacent highly antigenic N-terminal ofA� [152, 153] (Thomson Reuters Pharma, updates ofFebruary 7, 2013).

The development of etazolate (EHT-0202; SQ-20009; Diaxonhit, formerly Exonhit) and of NP-17,NP-21, NPM-01, NPM-05B1, and NPM-05B2 (orallyavailable �-secretase activators of marine origin;Noscira, Madrid) was terminated.

2.4. Drugs interacting with beta secretase

In the amyloidogenic pathway, A�PP is first cleavedby BACE1 (EC 3.4.23.46; [154, 155]) between residuemethionine 671 and aspartic acid 672 to release a100 kDa N-terminal fragment sA�PP and a 12 kDamembrane bound CFT99, which is subsequentlycleaved by �-secretase within the transmembraneregion to form C-terminal A� peptides ranging from38 to 43 residues. The splice variants of BACE1were reviewed [156]. The transcriptional and post-transcriptional regulation of BACE was described[157]. The normal and pathologic roles of �-secretaseBACE1 was described [732]. A physiological regula-tor of BACE 1 stability and activity is Rheb GTPase,which induced mammalian target of rapamycin activity[158].

There are many interesting reviews on the pharma-cology and medicinal chemistry of BACE inhibitors (inchronological order): 2012: [159], 2013: [160–162],2014: [163, 164].

MK-8931 (SCH-900931; Schering-Plough, nowMerck, Whitehouse Station, NJ; Fig. 6) is a potentinhibitor of BACE. Single doses of MK-8931 from2.5 to 550 mg were well-tolerated [165]. In November2013 a Phase III trial in prodromal AD patients wasinitiated in the US. In March 2014, the trial was ongo-ing in Australia, Canada, New Zealand, Japan, SouthKorea, France, and Spain (Thomson Reuters Pharma,update of May 27, 2014).

At the occasion of the 244th ACS meeting inPhiladelphia, Merck presented a bicyclic iminohetero-cycle compound (Fig. 6) with an optimized thiadiazinesubunit with high affinity for BACE. A full paper waspublished [166] (Thomson Reuters Pharma, update ofJuly 25, 2013).

AZD-3293 (Astex Pharmaceuticals, Dublin, CA,a wholly owned subsidiary of Otsuka Pharmaceuti-cal, Tokyo and AstraZeneca, London, UK; Fig. 6)is the lead compound from a program of BACEinhibitors. By December 2012, AZD-3293 was inPhase I in the US in healthy young and elderly volun-teers (expected n = 96). For medicinal chemistry, see

[167–172] (Thomson Reuters Pharma, update of April24, 2014).

CTS-21166 (ASP-1702, ATG-Z1; Astellas Pharma,Tokyo and CoMentis, South San Francisco, CA) is aBACE1 inhibitor in Phase I clinical trials since June2007. In 48 volunteers, the drug was safe and welltolerated (Thomson Reuters Pharma, update of January31, 2014). The structure was not communicated.

E-2609 (Eisai, Tokyo) is a BACE inhibitor in PhaseI clinical trials since December 2010 in the US inhealthy young and elderly volunteers (n = 48). The trialwas completed in May 2012. Multiple-ascending oraldoses of E-2609 (25 to 400 mg for 14 days) were stud-ied at a single site in the US in this ongoing trial inhealthy human volunteers of 50 to 85 years of age (bothgenders). The drug was safe and well tolerated withminor adverse effects. Reductions of A� in CSF andplasma were demonstrated following both single andrepeated administrations (Thomson Reuters Pharma,update of April 24, 2014). The structure was notcommunicated.

HPP-854 (TTP-854; High Point Pharmaceuticals,High Point, NC, a spin-out from TransTech Pharma,High Point, NC) is a BACE inhibitor in Phase I clin-ical trials since November 2009 (Thomson ReutersPharma, update of November 13, 2013). The structurewas not communicated.

Shionogi (Osaka, in collaboration with JanssenPharmaceuticals, Titusville, NJ, Fig. 6) is investigat-ing conformationally restricted BACE inhibitors [173,174]. In March 2013 the drug program was listed asbeing in Phase I in Europe (Thomson Reuters Pharma,update of June 6, 2014).

TAK-070 (University of Tokyo under license fromTakeda, Osaka; Fig. 6) is a BACE and A� aggregationinhibitor [175, 176]. By December 2013 a Phase I studywas underway (Thomson Reuters Pharma, update ofJanuary 28, 2014).

Vitae Pharmaceuticals (Fort Washington, PA) incollaboration with Boehringer Ingelheim and the Tech-nical University of Munich [208, 209] is exploringorally active BACE 1 inhibitors. In February 2014Phase I trials were initiated in the US and in Ger-many (Thomson Reuters Pharma, update of February21, 2014). Structures were not communicated.

Several BACE inhibitors of known structure are inpreclinical evaluation (in alphabetical order):

Amgen (Thousand Oaks, CA; Fig. 6) investigatedseries of 2-aminoquinolines and 2-aminopyridinesas BACE1 inhibitors including AMG-0683 [177].Hydroxy-ethylamine and aminoheterocyclic xan-thenes containing BACE inhibitors were described


Fig. 6. Beta-secretase inhibitors.

recently [178–182] (Thomson Reuters Pharma, updateof April 1, 2014).

Array BioPharma (Boulder, CO; Fig. 6) in collab-oration with Genentech (South San Francisco, CA)presented novel spirocyclic BACE1 inhibitors [183,184] (Thomson Reuters Pharma, update of January 23,2014).

AZ-4217 (AstraZeneca, Fig. 6) is a high potencyBACE1 inhibitor (IC50 = 160 pM). A one month treat-ment significantly lowered A� deposition in 12 monthold Tg2576 mice [185].

Scientists of the Beijing Institute of Pharmacologyand Toxicology presented the potent BACE1 InhibitorVIa (Fig. 6) with an IC50 = 5.9 nM for BACE1 andgood selectivites against BACE2, cathepsinD andrenin. In cellular assays 1 nM of BACE1 inhibitor VIareduced A�1-42 by 40% [186].

DIA-10-D (Arizona State University, Tempe, AZand the Roskamp Institute, Sarasota FL) is a bispe-cific tandem single chain (scFv) antibody combiningiBSEC1 with the ASec1A, which simultaneouslyinhibited BACE and promoted �-secretase processing


Fig. 7. Beta-secretase inhibitors II.

of A�PP. The iBSEC1 scFv was selected, since it rec-ognizes the BACE1 cleavage site on A�PP but doesnot bind the adjacent highly antigenic N-terminal ofA� [152, 153] (Thomson Reuters Pharma, updates ofFebruary 7, 2013).

ER-901356 (Eisai, Tokyo), a BACE1 inhibitor withan IC50 of 8 nM was administered to rats (3 and10 mg/kg po) and at 6 h the 10 mg/kg dose signifi-cantly reduced A�x-40 levels by 55%, 85%, and 70%in plasma, CSF, and brain, respectively. In Cynomol-gus monkeys administered 0.3 to 10 mg/kg p.o. ofER-901356, there was a dose-dependent reductionin plasma and CSF levels of A�1-40 reduction atthe highest doses was 87% and 60% in plasmaand CSF, respectively (Thomson Reuters Pharma,update of March 12, 2013). The structure was notcommunicated.

GNE-629 and GNE-892 (Genentech, South SanFrancisco, CA; both Fig. 6) are BACE inhibitors inpreclinical development [187–189].

GRL-8234 (Johns Hopkins University, Baltimore,MD and Georgetown University, Washington, DC,previously investigated by the Oklahoma MedicalResearch Foundation, Oklahoma City; Fig. 7) is apotent inhibitor of BACE (IC50 = 1.8 nM) and A� syn-thesis for the potential i.v. treatment of AD. It rescuedage-related cognitive decline in A�PP transgenic mice[190] (Thomson Reuters Pharma, update of March 17,2014).

HL-0362 (2,2′,4′-trihydroxychalcone; ShanghaiInstitute of Materia Medica of the Chinese Academyof Sciences), isolated from Glycyrrhiza glabra, a newinhibitor of BACE1 efficiently ameliorated memoryimpairment in mice [191]. Structure optimization iscurrently ongoing (Thomson Reuters Pharma, updateof September 11, 2013).

Johnson & Johnson (presumeably JNJ-715754,Fig. 7) is evaluating compounds from a series ofaminopiperazines with an IC50 of 40 nM in a BACE1enzymatic assay, of 28 nM for hA�42, and 25 nM forhA�Total. Medicinal chemistry papers were commu-nicated [192–197] (Thomson Reuters Pharma, updateof July 5, 2013).

L-655240 (Merck, Fig. 7) is a thromboxane A2antagonist, which was re-discovered as a BACE1inhibitor with IC50 of 4.47 �M by Chinese authors[198].

Novartis (Fig. 7) investigated a series of cyclicsulfoxide hydroxyethylamine BACE1 inhibitors. Thecompound reduced CSF and brain A�40 levels in adose-dependent manner and showed good efficacy ata 10 fold lower dose, when co-administered with theCYP3A4 inhibitor ritonavir in various animal mod-els. For medicinal chemistry, see [199–202] (ThomsonReuters Pharma, update of January 31, 2014).

Perrigo (Dublin, Ireland; following the acquisitionof Elan) is investigating a series of small-moleculeinhibitors of BACE1. Data on hydroxyethylamine


BACE1 inhibitors showed IC50 values against BACE1of 12 nM and an ED50 value of 2.1 nM in a HEK-293 cellular assay. Novel dihydroisoquinoline BACE1inhibitors were presented (Fig. 7) [203–205] (ThomsonReuters Pharma, update of December 19, 2013).

Pfizer scientists published on spirocyclic sulfamidesas BACE inhibitors (Fig. 7) [206, 207] (ThomsonReuters Pharma, update of August 2, 2013).

ProMediTech (Seoul)/LG Life Sciences (Seoul) andthe Seoul National University are investigating BACEinhibitors for the potential treatment of AD (Thom-son Reuters Pharma, update of November 8, 2013).Structures were not communicated.

Bi-functional small molecule inhibitors of �- and�-secretase (Hadassah University Hospital and theHadasit Medical Research Services and Development,Jerusalem) are investigated for the potential treat-ment of AD. In vitro data had demonstrated that twocompounds reduced amyloid-� levels in PC12 cellsin low micromolar concentrations (Thomson ReutersPharma, update of May 14, 2014).

Dual �7 nicotinic acetylcholine receptor acti-vators and BACE1 inhibitors are investigated in aprogram at the University of Maryland, College Park,MD (Thomson Reuters Pharma, update of November29, 2013). No structures were communicated.

BBS-1 BACE inhibitor mAb vaccine (NasVax,Ness Ziona, Israel under license from Ramot at TelAviv University) is investigating a vaccine based on itslead mAb candidate BBS-1 (blocking �-site-1), whichinhibits the ability of BACE1 to cleave A�PP (Thom-son Reuters Pharma, update of January 22, 2014).

Brain-targeted BACE1 antibody (Genentech, SouthSan Francisco, CA, Roche Holding) is a bi-specificantibody against BACE1 and the transferrin receptor toallow transcytosis across the blood-brain barrier (BBB)[210–212]. Safety liabilities of transferrin receptor bis-pecific antibodies that cross the BBB were addressed[213] (Thomson Reuters Pharma, update of July 26,2013).

Excellent papers on theoretical calculations onBACE1 inhibitors were presented (in chronologicalorder): 2013: [187, 214–216], 2014: [217].

The development of BACE inhibitors (Acte-lion, Bristol-Myers Squibb; [218–224]; the GeneticsCo (CallistoGen), Ligand, Locus Pharmaceuticals,Medivir [225, 226], Noscira and Plexxikon), GRL-11097 (Purdue University and Astellas Pharma),GSK-188909 (GSK; [227–235]), heparinoid �-secretase inhibitors (IntelliHep), LY-2886721 (EliLilly; [236–241]), PF-05297909 (Pfizer), RG-7129(Roche from a research collaboration with Siena

Biotech; [242–244]), and WAY-258131 (Wyeth, nowPfizer; [245–261]) was terminated.

2.5. Drugs interacting with gamma-secretase

�-secretase is an aspartyl protease that cleaves itssubstrates within the transmembrane region in a pro-cess termed regulated-intramembrae-proteolysis. Theenzyme consists of four protein components: prese-nilin 1 or 2, which contains the catalytic domain,nicastrin, Aph-1 (anterior pharynx-1), and Pen-2 (pre-senilin enhancer-2) in a 1 : 1:1 : 1 ratio [262].

There are many interesting publications on medic-inal chemistry and pharmacology of �-secretaseinhibitors and modulators (in chronological order):2012: [263, 264], 2013: [265], 2014: [266].

2.5.1. Gamma-secretase inhibitorsSeveral �-secretase inhibitors are in preclinical eval-

uation (in alphabetical order):FLZ is a synthetic cyclic derivative of

squamosamide from Annona glabra. It attenu-ated A�PP processing and decreased A� productionin mitochondria by selectively inhibiting �-secretase[267, 268].

Harvard Medical School scientists (Boston, MA)are investigating a series of Notch-sparing �-secretaseinhibitors for the potential treatment of AD (AD-1209, AD-1065, AD-1221, AD-1215, AD-1138, andAD-904; one structure shown in Fig. 8). One of thecompounds (AD-1068) had an IC50 value of 9 nMagainst A�42 and an IC50 value of 1.8 �M for Notch.An excellent review was published [269] (ThomsonReuters Pharma, update of July 25, 2013).

NGP-555 (NeuroGenetic Pharmaceuticals, DelMar, CA, Fig. 8) has an IC50 of 8.3 nM for A�. Itreduced levels of A�42 in brain and plasma at doses upto 100 mg/kg p.o. (Thomson Reuters Pharma, updateof March 22, 2013).

Pfizer (Ann Arbor, MI; Fig. 8) presented a novel�-secretase inhibitor containing a bicyclo-[1.1.1]-pentanyl moiety with an IC50 of 0.178 nM beingequipotent to avagacestat (IC50 = 0.196 nM) [270](Thomson Reuters Pharma, update of July 30, 2012).

RO-02 (Roche; Fig. 8) inhibited enzyme activitywith an A�42 inhibition IC50 value of 500 nM (Thom-son Reuters Pharma, update of April 30, 2013).

Inhibition of �-secretase activity by a monoclonalantibody against the extracellular hydrophilic loop ofpresenilin 1 was described [271].

Critical Outcome Technologies (London, Ontario) isinvestigating orally available, dual �- and �-secretase


Fig. 8. �-secretase inhibitors.

inhibitors for the potential treatment of AD (ThomsonReuters Pharma, update of January 29, 2013).

The development of many �-secretase inhibitorswas terminated (in alphabetical order), of avagaces-tat (BMS-708163; Bristol-Myers Squibb; [272– 289]),BMS-932481 (Bristol-Myers Squibb), E-2212 (Eisai;[290]), GSI-1 (L-685,458; SCH-900229; Merck;[291–297, 291, 298–315]), MK-0752 (Merck; termi-nated for the indication AD, but in Phase II for thetreatment of cancer [316]; Thomson Reuters Pharma,update of May 28, 2014); MRK-560 (SCH-1375975;Schering-Plough, now Merck; [291–293], [317–327]),NGP-328 (NeuroGenetic Pharmaceuticals), peptide-based �-secretase inhibitors (Pepscan Therapeutics),NIC5-15 (Humanetics under license from the MountSinai School of Medicine), PF-03084014 (Pfizer; ter-minated for the indication AD, but in Phase I forthe treatment of cancer; [328–331]; Thomson ReutersPharma, update of April 29, 2014).

2.5.2. Gamma-secretase modulators�-secretase modulator photoaffinity probes revealed

distinct allosteric binding sites on presenilin [332].�-secretase modulators were effective also in prepa-rations containing A�PP mutations [333].

Several reviews on �-secretase modulators werepresented (in chronological order): 2012: [334–336],2013: [337, 338], 2014: [339].

CHF-5074 (CereSpir, New York, NY under licensefrom Chiesi Farmaceutici, Parma; Fig. 9) is a �-secretase modulator in vitro and inhibited plaque

Fig. 9. �-secretase modulators.

deposition and reversed memory deficits in vivo intransgenic mouse models of AD. Tg2576 mice fedwith standard diet displayed an impairment of recogni-tion memory. This deficit was completely reverted afterlong term treatment with CHF-5074 for 13 months[340]. It restored visual memory ability [341] and inter-acted with the A�PP intracellular domain and impairedits nuclear activity [342].

In July 2012 data from the 12-week, double-blind,dose-range study were presented at the Alzheimer’s


Association International Conference 2012 in Vancou-ver, Canada. Patients were randomized to receive 200,400, and 600 mg of CHF-5074 p.o. daily (n = 72) orplacebo (n = 24). CHF-5074 was well tolerated. Pro-file of MCI and healthy patients were similar. The drugdose dependently affected CSF biomarkers of neuroin-flammation in man [343] (Thomson Reuters Pharma,update of April 2, 2014).

EVP-0962 (FORUM Pharmaceuticals, previouslyEnVivo Pharmaceuticals, Watertown, MA) is a �-secretase modulator in Phase I clinical evaluationsince June 2011 in healthy volunteers. By June 2012the Phase I trial was completed. In November 2012,a randomized, double-blind, parallel-assigned, PhaseII study was initiated in healthy subjects or sub-jects (expected n = 52) with MCI or AD in the USto assess the safety, tolerability, efficacy, and phar-macokinetics. Preclinical data on a close analogueEVP-0015962 were published recently [344] (Thom-son Reuters Pharma, update of April 3, 2014). Thestructures were not communicated.

Several �-secretase modulators are in preclinicalevaluation (in alphabetical order):

AS-2715348 (Astellas Pharma, Tsukuba; Fig. 9) isa �-secretase modulator, which reduced both cell-freeand cellular production of A�42 without increasing lev-els of A�PP �-carboxyl terminal fragment or inhibitingNotch signaling [345].

Asceneuron (Lausanne, Switzerland) investigatessmall A� peptides targeting �-secretase for thepotential treatment of AD (Thomson Reuters Pharma,update of July 18, 2013). The structures were notcommunicated.

BIIB-042 (Biogen Idec, Weston, PA; Fig. 9) isa �-secretase modulator, which significantly reducedbrain A�42 levels in CF-1 mice and in Fisher ratsand plasma A�42 levels in Cynomolgus monkeys(Thomson Reuters Pharma, update of March 27, 2012).

Dainippon Sumitomo Pharma (Osaka; Fig. 9) isevaluating �-secretase modulators for the potentialtreatment of AD. Medicinal chemistry was published[346] (Thomson Reuters Pharma, update of February25, 2014).

HCT-1026 (NicOx, Sophia-Antipolis, France;Fig. 9) is a nitric oxide (NO)-releasing flurbiprofenderivative. Recent research showed that it alle-viated functional muscle ischemia and may bevaluable to treat Duchenne muscular dystrophy [347](Thomson Reuters Pharma, update of November 13,2013).

The University of California San Diego is investigat-ing �-secretase modulators which inhibit the produc-

tion of A�42 for the potential treatment of AD [348](Thomson Reuters Pharma, update of June 13, 2013).

The development of �-secretase modulators ofAmgen [349] was terminated. Also the developmentof AZ1136, AZ-3303 and AZ-4800 (AstraZeneca;[350–354]), of SPI-014, SPI-1802, SPI-1810, andSPI-1865 (Satori Pharmaceuticals; [355–357]) and oftarenflurbil (MPC-7869; (R)-flurbiprofen, Flurizan,Myriad Genetics, Loma Linda University; [358–367])was discontinued.

2.5.3. Inhibitors of gamma-secretase activatingprotein

�-secretase activating protein (GSAP) interacts bothwith �-secretase and its substrate, the A�PP carboxy-terminal fragment (A�PP-CTF). The role of GSAP inthe regulation of �-secretase and A� generation wasreviewed [368].

Imatinib (Gleevec, STI-571; Novartis, launched in2001) is an inhibitor of GSAP. 3xTg mice treatedwith imatinib showed a significant reduction in GSAPexpression levels, brain A� levels and a reduction oftau phosphorylation [369].

ITI-009 series (Intra-Cellular Therapies, New York,NY) are GSAP inhibitors for the potential treatment ofAD. A previous compound IC-200155 is no longer fol-lowed up (Thomson Reuters Pharma, update of April8, 2014). Structures were not communicated.

2.5.4. Notch pathway inhibitorsAGT-0031 (AxoGlia Therapeutics, Luxembourg;

Fig. 10) is an inhibitor of the Notch pathway, which isinvolved in astrocyte differentiation and inflammatoryactivation for the potential treatment of MS and AD[370] (Thomson Reuters Pharma, update of February28, 2014).

2.6. Drugs interacting with aminoacylase 3

The University of California Los Angeles is inves-tigating aminoacylase 3 inhibitors for the potentialtreatment of AD, PD, and other neurodegenerative dis-eases. Inhibition of aminoacylase 3 protected cortexneuronal cells from the toxicity of 4-hydroxy-2-nonenal [371].

2.7. Drugs interacting with amyloid bindingalcohol dehydrogenase

The discovery that A�, present in mitochondria,specifically binds to amyloid binding alcohol dehydro-genase (ABAD) opened up a new area of AD research.


Fig. 10. A Notch pathway and three ACE inhibitor(s).

A recent review described the evidence that the pre-vention of A� binding to ABAD may be a valuabledrug target for the treatment of AD [372]. The firstpaper on structure-based design and synthesis of ben-zothiazole phosphonate analogues inhibiting humanABAD-A� was published by researchers of the Univer-sity of Kansas [373]. Small molecule ABAD inhibitorscrossing the BBB and their pharmacokinetics weredescribed [374].

2.8. Drugs interacting with angiotensinconverting enzyme (ACE)

Prelinical and clinical data of the topic ACE andmemory were discussed [375–378]. The use of ACEinhibitors in older adults with AD was associatedwith a slower rate of cognitive decline independentof hypertension as was shown in a four-year prospec-tive multicenter cohort study in France [379]. Centrallyacting ACE inhibitors reduced the rate of cognitivedecline in patients with dementia [380, 381]. Theprescription of ACE inhibitors is a protective factorfor cognitive deterioration [382]. Overexpression ofangiotensin-converting enzyme in myelo-monocytesprevented AD-like cognitive decline in mice [383].

Captopril (Capoten, Capozide; Bristol-MyersSquibb, launched in 1981; Fig. 10) attenuated the age-related decline in spatial learning and memory bothin spontaneously hypertensive rats as in Wistar-Kyotorats [384]. Captopril, but not losartan, a selective AT1receptor antagonist, improved learning in an activeavoidance task, whereas both drugs were effective in

enhancing retention of memory when administeredprior to the training of mice [385]. Captopril facilitatedmemory retrieval after a two month retention intervalin mice [386] and delayed the onset of scopolamine-induced impairment [387]. Captopril and enalaprilimproved cognition and depressed mood in hyperten-sive patients [388].

Perindopril (Aceon, Coversyl, Servier and KyowaHakko Kirin, launched in 1988; Fig. 10) is a long-acting ACE inhibitor. Several reports showed thatperindopril improved learning and memorizing in mice[389–393] and rats [394–396]. Perindopril did notshow any adverse cognitive effects in elderly [397].Perindopril was associated with a reduced rate of func-tional decline in patients with AD without associationwith mood or behavior suggesting that perindopril mayslow disease progression in AD [383].

Trandolapril (Gopten, Mavik, Odrik; Roussel-Uclaf, now sanofi, launched in Japan in 1993 and inthe US in 1997; Fig. 10) attenuated acquisition ofconditioned avoidance in rats [398]. Captopril and tran-dolapril improved learning and memory in active andpassive avoidance tests in rats comparable to the effectsof the nootropic drug oxiracetam [399].

2.9. Drugs interacting with beta-hexosaminidase

Amicus Therapeutics (Cranbury, NJ) was investi-gating small molecule pharmacological chaperonesthat bind to and activate the lysosomal enzyme beta-hexosaminidase for the potential oral treament of AD.These compounds lowered the levels of GM2 and


GM3 gangliosides associated with A� aggregation.The development was terminated (Thomson ReutersPharma, update of March 12, 2014).

2.10. Drugs interacting with 11beta-hydroxysteroid dehydrogenase

The topic 11�-hydroxysteroid dehydrogenase type1 (11�-HSD-1), brain atrophy, and cognitive declinewas reviewed [400].

UE-1961, UE-2811, and UE-2343 (Universityof Edinburgh in collaboration with Argenta Dis-covery, Harlow, UK; Fig. 11) are inhibitors of11�-hydroxysteroid dehydrogenase 1 (11�-HSD1)for the treatment of age-related cognitive disorders.UE-2343 showed cognition enhancement in agedtransgenic Tg2576 mice after one month of treatmentin a passive avoidance test and a significant reductionof their A� plaque load. In January 2013 a random-ized, double-blind, placebo-controlled Phase I study toassess safety, efficacy, pharmacokinetics, and pharma-codynamics in healthy subjects (expected n = 48) wasinitiated in the UK (Thomson Reuters Pharma, updateof September 26, 2013).

KR-1-2 (Korea Research Institute of ChemicalTechnology, Daejon, South Korea) suppressed cortisolby inhibiting 11�-hydroxysteroid dehydrogenase type1. The drug is intended for the treatment of glaucoma,non-insulin dependent diabetes, and dementia (Thom-son Reuters Pharma, update of December 2, 2013). Thestructure was not communicated.

The development of ABT-384 (Abbott Laborato-ries) was terminated [401].

2.11. Drugs interacting with calpain

Neuronal overexpression of the endogenousinhibitor of calpains, calpastatin, in [A30P] �-synuclein transgenic mice reduced human �-synucleinprocessing, aggregation, and synaptic impairment[402].

A-705253 (AbbVie, North Chicago, IL, a spin-out ofAbbott Laboratories, formerly Knoll, Bayreuth, Ger-many; Fig. 11) is an orally active calpain inhibitor forthe potential treatment of AD. A-705253 significantlyreduced cholinergic neurodegeneration caused by A�in a dose-dependent manner in rats [403–409]. It alsoprevented stress-induced tau hyperphosphorylation invitro and in vivo [410, 411] (Thomson Reuters Pharma,update of January 4, 2013).

ABT-957 (AbbVie, North Chicago, IL, a spin-outof Abbott Laboratories) is a calpain inhibitor for the

potential treatment of neurological disorders includingAD (Thomson Reuters Pharma, update of January 4,2013). The structure was not communicated.

AK-295 (CX-295, Vasolex; AxoTect, Atlanta, GAunder license from Cortex Pharmaceuticals, Irvine,CA, using technology licensed from Alkermes,Waltham, MA, Fig. 11) attenuated motor and cogni-tive deficits following experimental brain injury in therat [412]. According to CAS Reg. no. 160399-35-9, thesecond stereocenter was not defined (Thomson ReutersPharma, update of May 17, 2013).

Conjugated linoleic acid (CLA) is a �-calpain-specific inhibitor. CLA showed neuroprotective effectsagainst neurotoxins as A� in SH-SY5Y cells and inhib-ited A� oligomerization/fibrillation and A�-inducedZona Occludens-1 degradation [413].

SNJ-1945 (Senju Pharmaceutical Co, Osaka;Fig. 11) is a potent calpain inhibitor for the poten-tial oral treatment of age-related macular degeneration,retinopathy, and optic neuritis (Thomson ReutersPharma, update of March 25, 2013).

2.12. Drugs interacting with carbonic anhydrase

Carbonic anhydrase dysfunction impaired cognitionand was associated with mental retardation, AD, andaging [414].

The Blanchette Rockefeller Neurosciences Insti-tute (Morgantown, WV) is investigating phenylalaninecompounds acting as carbonic anhydrase activators forthe potential treatment of attention deficit disorders andmemory problems in AD (Thomson Reuters Pharma,update of April 18, 2014).

Ethylene bis-imidazoles are highly potent and selec-tive activators for isozymes VA and VII of carbonicanhydrase with potential nootropic effects [415].

2.13. Drugs interacting with carnitineacetyltransferase

Mildronate (THP, MET-88, Meldonium, Quaterine;Grindeks, Riga, Latvia; Fig. 11) is a launched carnitineacetyltransferase inhibitor [416] and nootropic drug,which improved cognition and reduced A� pathologyin transgenic AD mice [417–419].

2.14. Drugs interacting with caspases

Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases, are a family ofcysteine proteases that play essential roles in apoptosis(programmed cell death), necrosis, and inflammation.


Fig. 11. Two 11� hydroxysteroid dehydrogenase, three calpain, one carnitine acetyltranferase, one cathepsin B and one D-amino acid oxidaseinhibitor(s).

Caspase-6 activity predicts lower episodic memoryability in aged individuals [420, 421].

NWL-53 (New World Laboratories, Laval, Quebec)is a peptidomimetic and selective inhibitor of caspase-3 for the potential treatment of neurological diseasesincluding stroke, spinal cord injury, traumatic braininjury, MS, PD, AD, myocardial infarction, and can-cer (Thomson Reuters Pharma, update of January 24,2013). The structure was not communicated.

NWL-117 (New World Laboratories, Laval,Quebec) is an irreversible inhibitor of active caspase-6for the potential treatment of AD (Thomson ReutersPharma, update of July 18, 2012). The structure wasnot communicated.

NWL-149 (New World Laboratories, Laval,Quebec) is a selective caspase 1/4 modulator for thepotential treatment of inflammatory and autoimmunedegenerative diseases including MS, AD, and heartdisease (Thomson Reuters Pharma, update of January24, 2013). The structure was not communicated.

NWL-154 (New World Laboratories, Laval,Quebec) is a peptidomimetic and selective caspase6 modulator for the potential treatment of ADand Huntington’s disease (HD) (Thomson Reuters

Pharma, update of January 24, 2013). The structurewas not communicated.

2.15. Drugs interacting withcatechol-O-methyltransferase (COMT)

SOM-0226 (SOM Biotech, Barcelona) is the COMTinhibitor tolcapone for the potential oral prevention andtreatment of transthyretin amyloidosis in Phase II clin-ical trials since May 2012 in Spain (Thomson ReutersPharma, update of April 17, 2014).

Cerecor (Baltimore, MD under license from Merck)is investigating COMT inhibitors for the potential treat-ment of schizophrenia including cognition (ThomsonReuters Pharma, update of February 18, 2014). Struc-tures were not communicated.

Tolcapone (Tasmar; Roche, launched in 1997) andEntacapone (Comtan; Orion in collaboration withNovartis, launched in 1999) blocked fibril forma-tion of �-synuclein and A� and protected againstA�-induced toxicity [422]. Both agents acted as tau-derived hexapeptide (306)VQIVYK(311) aggregationinhibitors [423].


2.16. Drugs interacting with cathepsin

Decreased expression of Cathepsin D is related tothe defective degradation of amyloid-� in AD [733].

VBY-036 and VBY-129 (Virobay, Menlo Park, CA)are cathepsin S inhibitors for the potential oral treat-ment of AD. In May 2013 Virobay initiated a PhaseI, double-blind, randomized, placebo-controlled studyto evaluate escalating doses of VBY-036 in healthysubjects (Thomson Reuters Pharma, updates of Febru-ary 26, 2014 and March 13, 2013, respectively). Thestructures were not communicated.

Aloxistatin (E64d; AB-007; ALP-496; AmericanLife Science Pharmaceuticals, San Diego, CA; Fig. 11)is an inhibitor of cathepsin B for the potential treatmentof AD and traumatic brain injury [424]. E64d reducedbrain pyroglutamate A� [425]. Aloxistatin was pre-viously evaluated for the treatment of Duchennemuscular dystrophy by Taisho Pharmaceuticals, butthis development was terminated (Thomson ReutersPharma, update of April 8, 2014).

2.17. Drugs interacting with cholesterol24S-hydroxylase (CYP46A1)

Researchers elucidated the binding site of choles-terol within the A� peptide in the linear fragment22–35 of A� [426, 427]. For a debate, “is choles-terol a causative factor in AD”, see [428]. Two recentreviews deal with the role of cholesterol metabolismin the pathogenesis of AD [734, 735].

AAV-CYP46A1 (INSERM in collaboration withsanofi) is an adeno-associated virus gene ther-apy encoding cholesterol 24-hydroxylase (CYP46A1gene) for the potential injectable treatment of AD.Reduced A� peptides, amyloid deposits, and trimericoligomers were observed in A�PP23 mice. Significantimprovements in cognitive function assessed by theMorris water maze were also seen in Tau22 mice [429](Thomson Reuters Pharma, update of June 6, 2012).See also Part 3, Chapter 4. Drugs interacting with GeneExpression.

2.18. Drugs interacting with cyclooxygenase(COX)

COX (EC 1.14.99.1) is the enzyme responsiblefor the formation of prostaglandins, prostacyclin, andthromboxane. NSAIDs exert their effects through inhi-bition of COX.

COX-1 inhibition by SC-560 reduced amyloidpathology and improved memory deficits in a mousemodel of AD [430]. Short-term treatment with tolfe-

namic acid improved cognitive functions in AD mice[431]. It downregulated BACE1 after daily treatmentfor one month [432].

A review describes the use of anti-inflammatorydrugs in the therapy of AD [433].

A�42-lowering NSAIDs constitute the foundingmembers of the new class of �-secretase modulators,vide supra Chapter 2.5.2.

2.19. Drugs interacting with cytochrome P450(CYP) isoforms ( /= CYP46A1)

DX-0308 (Dermaxon, Missoula, MT) is an inhibitorof different CYP26 isoforms, which acts by inhibit-ing retinoic acid clearance for the potential treatmentof memory impairment associated with AD (ThomsonReuters Pharma, update of June 5, 2014). The structurewas not communicated.

2.20. Drugs interacting with D-Amino acidoxidase

Sodium benzoate, a D-amino acid oxidaseinhibitor, was tested in 60 patients with amnesticMCI and mild AD in Taiwan. The preliminary resultsshowed promise for D-amino acid oxidase inhibition asa novel approach for early dementing processes [434].

AS-2651816-00 (Astellas Pharma, Tokyo, Fig. 11)is a novel DAAO inhibitor for the potential treatmentof schizophrenia with an IC50 of 1.5 nM against humanDAAO [435] (Thomson Reuters Pharma, update ofJanuary 13, 2014).

Cerecor (Baltimore, MD) is investigating D-aminoacid oxidase (DAAO) inhibitors to enhance the activityof D-serine for the potential treatment of schizophre-nia (Thomson Reuters Pharma, update of August 12,2013). Structures were not communicated.

2.21. Drugs interacting with dipeptidyl-peptidase

Type 2 diabetes is one of the major risk factors asso-ciated with AD. Recent studies have found similaritiesin molecular mechanisms that underlie the respec-tive degenerative developments in the two diseases.Pharmacological agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase the level ofglucagon-like peptide-1 and ameliorate type 2 dia-betes, have become valuable candidates as diseasemodifying agents in the treatment of AD.

Saxagliptin (Onglyza; BMS-477118; OPC-262;Bristol-Myers Squibb and AstraZeneca, launched in2009; Fig. 12) ameliorated streptotocin-induced AD


in rats after oral treatment for 60 days [436] (ThomsonReuters Pharma, update of April 20, 2014).

Vildagliptin (Galvus, Jalra, Xiliarx, Equa; Novar-tis, launched in 2007; Fig. 12) is an orally activedipeptidylpeptidase IV (DPP IV) inhibitor for the treat-ment of diabetes. It ameliorated cognitive deficits andpathology observed in streptotocin-induced AD [437](Thomson Reuters Pharma, update of April 8, 2014).

2.22. Drugs interacting with glutaminyl cyclase

Glutaminyl cyclase (QC) is an enzyme that catalyzesthe formation of pyroglutamic peptides or proteinsfrom an N-terminal glutamine residue. When A� iscleaved between amino acids 2 and 3, a peptide with anN-terminal glutamate is formed, which is cyclized byQC to the N-terminal pyroglutamate. A review “Focus-ing the amyloid cascade hypothesis on N-truncatedA� peptides as drug targets against AD” was pub-lished [736]. Pyroglutamate-3 A� deposition in thebrains of humans, non-human primates, canines andAD-like transgenic mouse models was investigated[438]. The structural analysis of the pyroglutamate-modified isoform of the AD-related A� using NMRspectroscopy was described [439]. Pyroglutamylatedamyloid-� peptide reversed cross �-sheets by a prion-like mechanism [737]. Increased glutaminyl cyclaseexpression was found in peripheral blood of ADpatients [440]. Elevated pGlu-A� load showed a bet-ter correlation with the decline in Mini-Mental StateExamination scores than elevated concentration ofunmodified A� [441].

PQ-912 (Probiodrug, Halle Sachsen-Anhalt, Ger-many) is a potent QC inhibitor in Phase I clinicalstudies with single- and multiple ascending dose,blinded, placebo-controlled, randomized in healthyvolunteers (n = 100) since November 2011. In Novem-ber 2013 data from three Phase I, randomized,placebo-controlled, blinded, single- and multiple-ascending dose trials in >120 healthy volunteers werepresented at the 43rd SFN Meeting in San Diego, CA.Oral administration of PQ-912 was safe and well toler-ated with relevant therapeutic levels in blood and CSF.Pharmacokinetics was found to be dose-proportional(Thomson Reuters Pharma, update of February 17,2014). The structure was not communicated.

PBD-150 (Probiodrug, Halle, Sachsen-Anhalt, Ger-many; Fig. 12) is a potent inhibitor of humanglutaminyl cyclase (IC50 = 17 nM) and totally inhib-ited formation of A�3,11-(pE)40,42 in cell culture at1 �M (Thomson Reuters Pharma, update of March 7,2014).

A potential follow-up compound is PQ-1228 (Struc-ture was not communicated).

Novel benzimidazole derivatives were described(Fig. 12) [442]. One compounds had an IC50 value of0.07 �M and Ki value of 0.023 �M against human QC(Thomson Reuters Pharma, update of March 7, 2014).

2.23. Drugs interacting withglyceraldehyde-3-phosphate dehydrogenase

Omigapil (SNT-317, TCH-346, CGP-3466; San-thera, Liestal, Switzerland under license fromNovartis, Basel, Switzerland; Fig. 12) is an orallybioavailable glyceraldehyde 3-phosphate dehydroge-nase modulator with anti-apoptotic properties for thetreatment of PD and amyotrophic lateral sclerosis(ALS) in Phase I clinical trials since November 2011(Thomson Reuters Pharma, update of September 5,2013).

Glyceraldehyde 3-phosphate dehydrogenase-Siah cell death cascade inhibitors are investigatedby scientists of the Johns Hopkins University (Balti-more, MD) for the potential treatment of degenerativediseases like AD, PD, stroke, and cardiomyopathy(Thomson Reuters Pharma, update of March 13, 2014).Structures were not communicated.

2.24. Drugs interacting with glycogen synthasekinase-3β (GSK-3β)

GSK-3� (EC 2.7.11.26, 47 kDa) is a ser-ine/threonine protein kinase ubiquitously expressedand involved in many cellular signaling pathways play-ing a key role in the pathogenesis of AD [443]. Crucialis the phosphorylation at serine 9. The cited papers arelisted in chronological order: 2012: [444–451], 2013:[452], 2014: [453, 454].

There is currently no GSK-3� inhibitor in clinicaldevelopment, but there are many in preclinical evalu-ation (in alphabetical order):

AX-9839 (ActivX Biosciences, La Jolla, CA andKyorin Pharmaceuticals, Tokyo; Fig. 12) is an inhibitorof GSK-3� for the potential treatment of diabetes, AD,and various CNS disorders [455] (Thomson ReutersPharma, update of March 21, 2014).

Benfotiamine (a synthetic S-acyl derivative ofthiamine, i.e., vitamin B1, Shanghai Rixin Bio-Technology under license from Fudan University,Shanghai; Fig. 12) significantly reduced A� produc-tion in cells and enhanced the ratio of phosphorylatedGSK-3 together with consistent down-regulation ofGSK-3 activity. It showed beneficial effects on cog-


Fig. 12. Two dipeptidyl peptidase inhibitors, two glutaminyl cyclase inhibitors, a glyceraldehyde 3-phosphate dehydrogenase modulator and 9GSK-3� inhibitors.

nitive impairment and A� deposition in A�PP/PS1transgenic mice [456, 457]. In July 2013, an IND wasfiled in China (Thomson Reuters Pharma, update ofApril 24, 2014).

Bristol-Myers Squibb is investigating novel ison-icotinamides as selective GSK-3 inhibitors for thepotential treatment of AD. The lead compound inhib-ited GSK-3� and � with IC50 values of 0.3 and


0.9 nM, respectively, and lowered hyperphosphoryla-tion of tau with an IC50 value of 40 nM (ThomsonReuters Pharma, update of March 26, 2014). Structureswere not communicated.

Celon Pharma (Lomianki, Poland) is investigatinga GSK-3� inhibitor for the potential treatment of AD(Thomson Reuters Pharma, update of March 14, 2013).The structure was not communicated.

Cyclacel Pharmaceuticals (Berkeley Heights, NJ;Fig. 12) is investigating GSK-3� inhibitors for thepotential oral treatment of type 2 diabetes [458](Thomson Reuters Pharma, update of December 27,2013).

Dual GSK-3/casein kinase (CK) 2 modulators(University of Illinois at Chicago and the University ofIllinois at Urbana-Champaign) are investigated for thepotential treatment of AD (Thomson Reuters Pharma,update of November 4, 2013). Structures were notcommunicated.

JGK-263 (JI-7263, JGK-216; Jeil Pharmaceuti-cals, Seoul in collaboration with the Seoul NationalUniversity, Hanyang University and Daegu Haany Uni-versity) is the lead compound from a series of GSK-3�inhibitors for the potential treatment of AD and ALS(Thomson Reuters Pharma, update of December 4,2013). The structure was not communicated.

L803-mts and GSC-7 (Tel Aviv University andthe Weizmann Institute, Rehovot, Israel) are peptidicGSK-3 inhibitors, which on nasal treatment reducedA� burden and improved cognitive effects in 5xFADmice (Thomson Reuters Pharma, update of January 22,2014).

Mitsubishi Tanabe Pharma (Osaka; Fig. 12) isinvestigating GSK-3� inhibitors from a series of 2-(2-phenylmorpholin-4-yl) pyrimidin-4(3H)-ones [459,460]. The most potent compound had an IC50 value12 nM and clearance value of 0.06 ml/min/mg ina human liver microsome assay. In male rats thecompound demonstrated significant decrease of tauphosphorylation after oral administration in miceand also exhibited excellent pharmacokinetic profiles(Thomson Reuters Pharma, update of March 5, 2014).

NNI-362 (NNI-AD; NeuroNascent, Clarksville,MD in collaboration with the National Institute onAging, Bethesda, MD) is a multikinase and GSK-3�modulator inhibiting several tau phosphorylation sites.Other orally active compounds that stimulate neuronformation are NNI-X01, NNI-C, and NNI-251 (Thom-son Reuters Pharma, update of April 23, 2014). Nostructure was communicated.

Pfizer (Fig. 12) investigated a series of oxazolederivatives. The shown compound had an IC50 of 5 nM

and a more than 100-fold selectivity against all otherkinases and met safety criteria [461] (Thomson ReutersPharma, update of August 28, 2012).

SN-2127 (AstraZeneca, Fig. 12) is one of severalGSK-3� inhibitors in evaluation by AstraZeneca as areSN-2568, SN-3728, and others [462, 463] (ThomsonReuters Pharma, update of April 5, 2012).

Takeda (Osaka) presented very potent GSK-3�inhibitors with 1,3,4-oxadiazole structures with IC50values of 2 nM [464–466]. The chiral sulfoxideMMBO (Fig. 12) decreased tau phosphorylation andameliorated cognitive deficits in a transgenic model ofAD [467].

TWS-119 (Scripps Research Institute, La Jolla, CA;Fig. 12) is a compound that induced neurogenesis inmurine embryonic stem cells. The target of TWS-119was shown to be GSK-3� by affinity-based and bio-chemical methods [468].

UDA-680 (SAR-502250; Mitsubishi Pharma,Osaka and sanofi, Paris) is a GSK-3� and tauphosphorylating kinase 1 inhibitor for the potentialtreatment of AD and schizophrenia (Thomson ReutersPharma, update of November 11, 2013). The structurewas not communicated.

VP1.15 (CSIC, Madrid and the University ofToronto, Fig. 12) is a dual GSK-3 and PDE7 inhibitoracting as an antipsychotic and cognitive enhancer inC57BL/6J mice [469, 470].

Potent GSK-3� inhibitors were described byresearchers at universities (in alphabetical order oftheir location): Technical University of Darmstadt[471], Martin-Luther University Halle [472–474],Zhejiang University of Technology, Hangzhou, China[475, 476], CSIC Madrid [477–480], Hanyang Uni-versity College of Medicine, Seoul [481], FudanUniversity Shanghai [482–484], and Tel Aviv Univer-sity [485].

SAR studies on GSK-3� inhibitors were publishedby a joint effort of researchers from the Technical Uni-versity Darmstadt, University of Naples, University ofLeuven and Tel Aviv University [486].

DM-204 (DiaMedica, Minneapolis, MN followingits acquisition of Sanomune, Winnipeg, Manitoba)is a monoclonal antibody that inhibits GSK-3� forthe potential treatment of cancer, diabetes, influenza,hypertension, and neuronal disorders such as AD, HD,and tularemia (Thomson Reuters Pharma update ofJanuary 23, 2014).

The development of allosteric inhibitors of GSK-3� (Broad Institute) and of AZD-1080 (AstraZeneca)was terminated [487–490], but it is re-investigatedby scientists from the University of Leeds for the


potential treatment of glioblastoma; Thomson ReutersPharma, update of June 14, 2013). Also terminated wasthe development of CG-9, CG-701338, CG-701446,and CG-701448 (CrystalGenomics), CHIR-98014(Chiron, Novartis), CP-70949 (Pfizer; [491]) andof NP-101020 and tideglusib (Noscira, previouslyknown as Neuropharma; [492–495].

2.25. Drugs interacting with guanylyl cyclase

Activation of soluble guanyl cyclase and cGMP for-mation in the brain represents one element of effectiveneuroprotective pathways mediated by NO [496].

sGC-1061 (sGC Pharma, Cambridge, MA) is asustained-release NO-mimetic and nomethiazole forthe potential treatment of AD in Phase I clinicaltrial, which was completed in July 2012 show-ing high bioavailability (Thomson Reuters Pharma,update of March 4, 2014). The structure was notcommunicated.

2.26. Drugs interacting with heme oxygenase

OB-28 (Osta Biotechnologies, Dollard-des-Ormeaux, Quebec) was a heme oxygenase-1 inhibitorfor the potential injectable treatment of AD showingstatistically significant improvement in behavioraldeficits in double transgenic (A�PPSWE/PS1dE9)mice (n = 103) after treatment with 15 or 30 mg/kg/dayfor 4 months. The development was terminated(Thomson Reuters Pharma update of April 4, 2013).

2.27. Drugs interacting with histone deacetylases( /= Sirtuins)

The potential of HDAC inhibitors as cognitiveenhancers was discussed [497, 498]. The loss ofHDAC5 impaired memory function [499]. The classIII histone deacetylases, sirtuins 1–7, are described inChapter 2.56.

FRM-0334 (formerly EVP-0334; FORUM Pharma-ceuticals, previously EnVivo, Watertown, MA underlicense from MethylGene, Montreal) is developing theorally active HDAC inhibitor as a cognition enhancerfor the potential treatment of AD. Phase II trials areunderway since November 2011 (Thomson ReutersPharma, update of June 3, 2014). The structure wasnot communicated.

Other HDAC inhibitors are currently in preclinicalevaluation (in alphabetical order):

CHDI-390576 and CHDI-00381817 (HDAC4inhibitors; Fig. 13) are investigated by the CHDI

Foundation (Los Angeles, CA) in collaboration withBioFocus DPI (Saffron Walden, Essex, UK) for thepotential treatment of HD (Thomson Reuters Pharmaupdate of February 12, 2014).

Crebinostat (Harvard University Medical School,Boston, MA; Fig. 13) is a novel HDAC inhibitor andenhancer of CREB-regulated transcription and modu-lator of chromatin-mediated neuroplasticity [500].

Entinostat (MS-275, SNDX-275; Syndax Phar-maceuticals, Waltham, MA under license fromBayer Schering Pharma, Berlin; Fig. 13) amelioratedmicroglial activation and A� deposition in the cerebralcortex of transgenic A�PP/PS1 mice [501].

HDAC inhibitors (BioMarin, Novato, CA, throughan asset acquisition from RepliGen, Waltham, MAunder license from the Scripps Research Institute,La Jolla, CA; Fig. 13 shows KJ-106B) is investigat-ing a series of HDAC-1, -3, and -4 inhibitors, thatreverse FXN (frataxin-encoding gene) silencing forthe potential oral treatment of neurological disorders,including memory disorders and Friedreich’s ataxia[502, 503]. The Scripps Institute disclosed severalcompounds including KJ-81B, KJ-82B, KJ-102B, andKJ-106B (Thomson Reuters Pharma update of January22, 2014).

LB-201 and LB-205 (Lixte Biotechnology, EastSetauket, NY, Fig. 13) target HDAC and preventthe degradation and restore the activity of glucocere-brosidase for the potential treatment of neurologicaldisorders, as Gaucher’s disease and traumatic braininjury [504] (Thomson Reuters Pharma update ofFebruary 25, 2013 and July 25, 2013, respectively).

Quinazolin-4-one derivatives are selective HDAC6inhibitors for the treatment of AD [505].

Sodium butyrate, a pan-HDAC inhibitor, improvedmemory function in an AD mouse model [506, 507]. Itimproved cognitive impairments induced by isofluraneexposure in aged rats [508].

Sodium valproate, a class I HDAC inhibitor (i.e.,HDAC1,2,3,8), completely restored contextual mem-ory in a mouse model of AD [509–511].

Trichostatin A induces the protein expression ofgelsolin, which binds to A� and inhibits its fibrillation[512].

Tubastatin A (Fig. 13) is a potent and selectiveHDAC6 inhibitor [513]. Chronic tubastatin A treat-ment for two months decreased total tau levels intg4510 mice [514]. HDAC6 inhibition resulted intau acetylation and modulated tau phosphorylation[515].

The development of KAR-3010, KAR-3084,and KAR-3166 (Karus Therapeutics) and of


Fig. 13. Histone Deacetylase inhibitors.

4-Phenylbutyrate (Digna Biotech SL, [516–522])was terminated.

2.28. Drugs interacting with HMG-CoA reductase

The enzyme 3-hydroxy-3-methyl-glutaryl-CoAreductase (EC 1.1.1.88) is the rate-controlling enzymeof the mevalonate pathway, which produces choles-terol and other isoprenoids. It is the target of thestatins (or HMG-CoA reductase inhibitors). Statinsare more than cholesterol lowering agents in AD[523]. A systematic review on statins and cognitivefunction was published [524].

In September 2009 a randomized, double blind, par-allel assignment, treatment, safety/efficacy, Phase Itrial of lovastatin oral capsule began in the US inpatients (expected n = 50) with neurofibromatosis typeI. By May 2013 data had demonstrated that lovastatinwas safe and well tolerated in children and had shownimprovements in memory. By May 2013 a Phase II trialhad been initiated by the University of California LosAngeles (UCLA).

NST-0037 (Neuron BioPharma, Granada, Spain;Fig. 14) is a natural HMG-CoA-reductase inhibitor,which displayed neuroprotective, antioxidant, and

anti-convulsive activities. The synthesis was described[525]. Potential follow-up compounds are NST-0005and NST-0060 (for both Thomson Reuters Pharma,update of December 26, 2013), whereas the develop-ment of NST-0021 was terminated.

Atorvastatin (Lipitor, Pfizer, launched in 1996)prevented amyloid-� peptide oligomer-induced synap-totoxicity and memory dysfunction in rats through ap38 MAPK-dependent pathway [738].

2.29. Drugs interacting with insulin-degradingenzyme

Inventram (Istanbul, Turkey) is investigatinginsulin-degrading enzyme activators for the potentialtreatment of type 2 diabetes and AD (Thomson ReutersPharma, update of March 13, 2014). Structures werenot communicated.

2.30. Drugs interacting with insulin-regulatedaminopeptidase

Insuline-regulated aminopeptidase (IRAP) is themain target of the hexapeptide angiotensin IV(Ang IV), which on intracerebroventricular injection


Fig. 14. One HMG-CoA-reductase, 13 kinase, one kynurenine aminotransferase II and one monoacylglycerol lipase inhibitor(s).


improved memory and learning in rats [526–528].Deletion of the IRAP gene resulted in mice with anaccelerated, age-related decline in spatial memory thatwas only detected in the Y maze paradigm [529].It was proposed to search for inhibitors of IRAP aspotential enhancers of cognitive function [530–533].Recently a novel radioligand for IRAP [3H]IVDE77was described [534].

2.31. Drugs interacting with kinases ( /= GSK-3β

and /= PKC)

Masitinib (AB-1010, AB Science, Paris, France;Fig. 14) is an inhibitor of c-kit, Lyn, and PDGF-Rkinases. It was evaluated in a Phase II clinical trial asan adjunct therapy to cholinesterase inhibitor and/ormematine in 26 patients with mild-to-moderate ADversus placebo (n = 8). The masitinib treated patientsshowed improvements in Mini-Mental State Exam-ination scores, the Alzheimer’s Disease AssessmentScale-cognitive subscale, and the AD CooperativeStudy Activities of Daily Living Inventory with sta-tistical significance between treatment arms at week12 and/or week 24 (p = 0.016 and 0.030, respectively)[535]. In September 2010, EMA approved a pivotalPhase III trial in 300 AD patients to assess safetyand efficacy of 6 mg/kg/day masitinib over 24 weeks.The biological characterization was described [536].Masitinib is in the Pre-registration Phase in Europe forthe treatment of gastro-intestinal tumors since Octo-ber 2012. Masitinib will also be tested in ALS patients(Thomson Reuters Pharma, update of June 2, 2014).

PLX-5622 (Plexxikon, Berkeley, CA, a subsidiaryof Daiichi Sankyo, Tokyo) is a fms kinase inhibitorinvestigated for the potential oral treatment of rheuma-toid arthritis, MS, and AD in Phase I clinical trials forrheumatoid arthritis since January 2011 and for AD andMS since November 2013 in the US (Thomson ReutersPharma, update of March 24, 2014). The structure wasnot communicated.

Saracatinib (AZD-0530, NSC-73464,AstraZeneca, University of Sheffield and YaleUniversity) is a dual Src/Abl tyrosine kinase inhibitor,which was tested in Phase II clinical trials for the treat-ment of solid tumors. Yale University researchers areinvestigating saracatinib for the potential treatment ofAD. In July 2013 a Phase I trial was initiated in the US(Thomson Reuters Pharma, update of April 29, 2014).

Many other kinase inhibitor therapeutics are cur-rently in preclinical evaluation (in alphabetical order)for the potential treatment of neurodegenerativediseases:

Apoptosis signal-regulating kinase 1 (ASK1)inhibitors are investigated by Takeda (Osaka) for thepotential treatment of various indications includingautoimmune diseases, diabetes, inflammatory disor-ders, cardiovascular disease, and neurodegenerativedisorders [537] (Thomson Reuters Pharma, update ofMay 14, 2014).

Beta carboline alkaloids as harmol (Fig. 14)inhibit dual specificity tyrosine phosphorylation reg-ulated kinase 1A (DYRK1A) and tau phosphorylation(IC50 = 90 nM). DYRK1A enhanced tau expression ina dose-dependent manner [538].

Cadeprin (group S8A serine protease) antagonistsare investigated by researchers from the Universitiesof Strathclyde and Glasgow [539] (Thomson ReutersPharma, update of December 4, 2012). Structures werenot communicated.

Casein kinase 1δ inhibitors (NB Health Labo-ratory, Sapporo in collaboration with Mercachem,Nijmegen, the Netherlands) are investigated for thepotential treatment of AD (Thomson Reuters Pharma,update of May 31, 2013) Structures were notcommunicated.

Casein kinase 1 δ inhibitors (Proteome Sciences,Cobham, Surrey, UK), such as PS-110 and PS-278,are investigated for the potential treatment of AD.In September 2013 preclinical data were presented(Thomson Reuters Pharma, update of May 29, 2014).Structures were not communicated.

Cdc2-like kinases (Clk) and dual-specificitytyrosine-regulated kinase 1A (DYRK1A) inhibitorsare investigated by researchers of the National Cen-ter for Advancing Translational Sciences (NCATS;Bethesda, MD) for the potential treatment of Down’ssyndrome and AD (Thomson Reuters Pharma, updateof May 28, 2013). Structures were not communicated.

CDK5/CDK2 inhibitory peptides (Hong KongUniversity of Science and Technology) are evaluatedfor the potential treatment of AD (Thomson ReutersPharma, update of January 8, 2014). Structures werenot communicated.

CDK5/p25 inhibitors (AstraZeneca, the lead com-pound in shown in Fig. 14) are investigated for thepotential treatment of AD. Medicinal chemistry waspublished [540] (Thomson Reuters Pharma, update ofFebruary 13, 2013).

CLFB-1134 (Califia Bio, San Diego, CA) is asecond generation selective mixed lineage kinase-3inhibitor for the potential treatment of HIV-associatedneurocognitive disorder. (Thomson Reuters Pharma,update of November 15, 2013). The structure was notcommunicated.


Dasatinib (Bristol-Myers Squibb, launched in2006), a Src tyrosine kinase inhibitor, attenuated A�associated microgliosis in a murine model of AD[541].

Eukaryotic elongation factor-2 kinase (eEF2K)inhibitors (Johns Hopkins University, Baltimore, MD)are investigated for the potential treatment of AD,Down’s syndrome and fragile X mental retardationsyndrome (Thomson Reuters Pharma, update of March14, 2014). Structures were not communicated.

FRAX-120, FRAX-355, and FRAX-486 (Afraxis,La Jolla, CA and The Scripps Research Institute, LaJolla, CA) showed IC50 values of 23, 58, and 14 nMfor p21-activated kinase (PAK). The drugs have apotential for the treatment of fragile X syndrome,autism, schizophrenia, and AD. The rescue of frag-ile X syndrome phenotypes in Fmr1 knockout miceby the small-molecule PAK inhibitor FRAX-486 wasdescribed [542] (Thomson Reuters Pharma, update ofMay 29, 2014). The structure of FRAX-597 (Fig. 14)was communicated.

Fyn kinase inhibition may provide a novel therapyfor AD [543].

G-2019S (Zenobia Pharmaceuticals, San Diego,CA, in collaboration with Johns Hopkins Univer-sity, Baltimore, MD) is a leucine-rich repeat kinase-2(LRRK2) inhibitor for the potential treatment of PD(Thomson Reuters Pharma, update of January 27,2014). The structure was not communicated.

GNE-7915 (Genentech, South San Francisco, CA,and BioFocus, Saffron Walden, Essex, UK; Fig. 14) isa LRRK2 inhibitor for the potential treatment of PD.Medicinal chemistry was described [544, 545] (Thom-son Reuters Pharma, update of October 15, 2013).

GSK-2606414 and GSK-2656157 (GSK; Fig. 14)are protein kinase receptor-like endoplasmic reticu-lum kinase inhibitors for potential treatment of solidtumors and neurodegenerative diseases including AD.Biological data were published [546]. For an excel-lent commentary, see [547]. Medicinal chemistry wasdescribed [548] (Thomson Reuters Pharma, update ofJanuary 23, 2014).

Hydroxy-fasudil (Asahi Kasei Pharma Corp.,Tokyo), a rho kinase (ROCK) inhibitor, improved spa-tial learning and working memory in rats in a waterradial-arm maze [549]. Fasudil protected against A�-induced hippocampal neurodegeneration in rats [550].ROCK inhibition led to an increase of Rac1 activity andto an activation of PKCζ which in turn phosphorylatedKIBRA involved in the formation of memory [551].ROCK inhibition prevented tau hyperphosphorylation[552].

Imatinib (Gleevec, STI-571; Novartis, launched in2001) is an inhibitor of tyrosine kinases includingBcr-Abl and c-kit. Imatinib eliminated the cognitiveimpairment seen following seven consecutive days ofLPS-induced peripheral inflammation implicating A�peptides as a likely cause of these cognitive deficits[553, 554].

ITI-012 series (Intra-Cellular Therapies, New York,NY) are casein kinase I inhibitors for the potential treat-ment of AD (Thomson Reuters Pharma, update of April8, 2014). The structures were not communicated.

LRRK2 inhibitors (Oncodesign Biotechnology,Dijon, France) are investigated for the potential treat-ment of cancer and CNS diseases including PDutilizing its Nanocyclix technology (Thomson ReutersPharma, update of April 30, 2013). Structures were notcommunicated.

LRRK2 inhibitors (Origenis GmbH, Martinsried,Bavaria) are investigated for the potential treatmentof PD (Thomson Reuters Pharma, update of April 7,2014). Structures were not communicated.

LRRK2 inhibitors (Perrigo, formerly Elan Phar-maceuticals, Dublin, Ireland) on novel cinnolinescaffolds were published recently [555]. Also tria-zolopyridazine and cyano-quinoline LRRK2 kinaseinhibitors were presented [556, 557].

LRRK2 inhibitors (SignalChem Life Sciences,Richmond, BC, formerly MetSignal) are investigatedfor the potential treatment of PD and AD (ThomsonReuters Pharma, update of March 25, 2013). The struc-tures were not communicated.

LRRK2 inhibitors (Vernalis, Winnersh, UK incollaboration with Lundbeck, Valby, Denmark) areinvestigated for the potential treatment of PD (Thom-son Reuters Pharma, update of May 23, 2013). Thestructures were not communicated.

For LRRK2 interactions with �-synuclein in PDbrains and in cell models, see [558].

MARK inhibitors (microtubule affinity regulatingkinase inhibitors; Medical Research Council Technol-ogy, London) are investigated for the inhibition oftau phosphorylation. The role of individual MARKisoforms in the phosphorylation of tau at Ser262was investigated [559] (Thomson Reuters Pharma,update of November 1, 2013). Structures were notcommunicated.

MARK inhibitors (Merck Research Laboratories,Boston, MA) are in preclinical evaluation for the poten-tial treatment of AD. The compound in Fig. 14 showedpotent activity with IC50 values of 3 and 56 nM againstMARK 3 and 4, respectively. In rats it showed t1/2and bioavailability values of 3.5 h and 46%, respec-


tively (Thomson Reuters Pharma, update of August29, 2012).

Minokine (MW01-2-069A-SRM; NorthWesternUniversity, Evanston, IL; Fig. 14) is a p38 MAP kinaseinhibitor for the potential oral treatment of neurode-generative diseases including AD (Thomson ReutersPharma, update of November 22, 2013). Structure-and ligand-based drug design of novel p38-a MAPKinhibitors for the treatment of AD were disclosed[560].

MW-108 (MW01-11-108SRM; NorthWestern Uni-versity, Evanston, IL in collaboration with theUniversity of Kentucky, Lexington, KY and ColumbiaUniversity, New York, NY; Fig. 14) is a CNS-activep38-�MAP kinase inhibitor [561]. MW-108 improvedA�-induced synaptic and cognitive dysfunction, bothin vitro and in vivo (Thomson Reuters Pharma, updateof December 24, 2013).

Nilotinib (AMN-107, Tasigna; Novartis, launchedin 2007) is an oral inhibitor of Bcr-Abl, c-Kit, PDGFR,DDR and related receptor tyrosine kinases. It causedA� clearance via an increase of endogenous parkinlevels and ubiquitination [562].

NNI-351 (NNI-depression; NNI-DS; Neu-roNascent, Clarksville, MD; Fig. 14) is a dualspecificity tyrosine-phosphorylation-regulated kinase1� (DYRK1�) inhibitor for the potential treatment ofdepression and Down’s syndrome. The orally activecompound prevented stress-induced neurogenesisreduction (Thomson Reuters Pharma, update of April23, 2014).

ORS-1104 (Arrien Pharmaceuticals, Somerset, NJ)is the lead compound from a program comprising twoseries of LRRK2 inhibitors for the potential oral treat-ment of PD. For a review, see [563] (Thomson ReutersPharma, update of January 15, 2014). The structurewas not communicated.

P-005 (NB Health Laboratory, Sapporo) is a smallmolecule casein kinase 1 delta (CK-1δ) inhibitor for thepotential oral treatment of sleep disturbances includingcircadian rhythm disorder, in patients with dementia(Thomson Reuters Pharma, update of November 27,2013). The structure was not communicated.

Inhibitors of the protein kinase c-raf1, such as GW-5074 and ZM-336372, protected cortical cells againstA� toxicity [564].

Protein kinase inhibitors (ManRos Therapeutics,Roscoff, Bretagne, France, leucettine-L41 is shownin Fig. 14) are evaluated as AD medication. Selectiv-ity, cocrystal structures and neuroprotective propertiesof leucettines, a family of protein kinase inhibitorsderived from the marine sponge alkaloid leucettamine

B, were published [565–567] (Thomson ReutersPharma, update of March 7, 2014).

SEL-141 (Selvita Life Sciences Solutions, Krakow,PL) is a program targeting DYRK1A kinase and otherkinases involved in tau hyperphosphorylation includ-ing SLV-01917, SLV-00251, SLV-00125, SLV-00756,SLV-00095, and SLV-01184 for the potential treatmentof AD, cancer, and neurological diseases, includingDown syndrome, tauopathy, and cognitive diseases(Thomson Reuters Pharma, update of May 23, 2014).Structures were not communicated.

SKI-G-1141 (Genosco, a subsidiary of Oscotec,Buena Park, CA) is a LRRK2 inhibitor for thepotential treatment of PD (Thomson Reuters Pharma,update of September 17, 2013). The structure was notcommunicated.

Sorafenib, a small molecular inhibitor of tyrosineprotein kinases (VEGFR and PDGFR) and of raf,restored working memory in A�PPSWE transgenicmice [568].

Sphingosine kinase-1 protected differentiated N2acells againist A�25-35-induced neurotoxicity via themitochondrial pathway [569].

T-343 (Arizona State University, Tempe, AZ andTranslational Genomics Research Institute, Phoenix,AZ) is a Rho-associated protein kinase (ROCK) I/IIinhibitor, for the potential treatment of AD [549]. Itshowed IC50 values of 1.2 and 0.3 �M against ROCK-Iand -II, respectively. In H4-tau cells the ratio of p-tau tototal tau was significantly reduced (Thomson ReutersPharma, update of November 22, 2013). The structurewas not communicated.

TFP-5 (National Institute of Neurological Disordersand Stroke, Bethesda, MD) is a modified truncated pep-tide from p35, a CDK5 activator, which prevented ADphenotypes in a 5xFAD AD mouse model [570, 571](Thomson Reuters Pharma, update of May 10, 2013).The structure was not communicated.

TTBK1 inhibitors (SignalChem Life Sciences,Richmond, BC, formerly MetaSignal), tau-tubulinkinase 1 inhibitors, are investigated for the potentialtreatment of PD and AD (Thomson Reuters Pharma,update of March 25, 2013). Structures were notdisclosed.

TTT-3002 (TauTaTis, Jacksonville, FL) is a multi-targeted kinase inhibitor that can inhibit the LRRK2gene and tumor growth for the potential treatmentof PD, AD, and cancer (Thomson Reuters Pharma,update of November 27, 2013). The structure was notcommunicated.

University of Arizona (Tucson, AZ) chemists in col-laboration with the Translational Genomics Research


Institute (Phoenix, AZ) described advances in thesearch for novel DYRK1A inhibitors [572] (ThomsonReuters Pharma, update of November 7, 2013).

URMC-099-C (Califia, San Diego, CA, the Uni-versity of Nebraska Medical Center, Omaha, NEand the University of Rochester, NY; Fig. 14) isan inhibitor of mixed lineage kinase-3 for the treat-ment of HIV-associated neurocognitive disorder [573](Thomson Reuters Pharma, update of March 19,2014).

The development of AIK-2, AIK-2a, AIK-2c, andAIK-21 (Allinky Biopharma), CDK5/p25 inhibitors(Pfizer; [574, 575]), CEP-1347 (a mixed lineagekinase-1 inhibitor; Cephalon), CZC-25146 (Cell-zome; [576]), dual-specificity tyrosine-regulatedkinase (DYRK) 1�/1� inhibitors (Diaxonhit, for-merly ExonHit), GSK-2578215A (GSK), KIBRApathway modulators (Amnestix; [551, 577–579]),LDN-22684 (a LRRK2 inhibitor; Sirtris Pharmaceuti-cals; [580]), LRRK2 inhibitors (Pfizer), PLX-3397(an oral small-molecule dual Fms/kit and Flt3-ITDinhibitor; Plexxikon; a Phase II trial for the treatmentof acute myelogenous leukemia continues; ThomsonReuters Pharma, update of June 2, 2014) was termi-nated.

2.32. Drugs interacting with kynureninemono-oxygenase and kynureninetransaminase II

For the potential role of kyurenines in dementia andAD, see [581, 582]. Targeting the kynurenine pathway-related alterations in AD may be a future therapeuticstrategy [583, 584]. The X-ray structure of kynurenine-3-monooxygenase in complex with the tight-bindinginhibitor UPF-648 was resolved [585].

CG-026864 (CrystalGenomics, Seongnam, SouthKorea) is a small molecule kynurenine mono-oxygenase (KMO) inhibitor for the potential oraltreatment of neurodenegenative diseases such as HDand AD (Thomson Reuters Pharma, update of Novem-ber 29, 2013). The structure was not communicated.

CHDI-003940246 and CHDI-00340246 (Evotec,Hamburg, in collaboration with the CHDI Foundation,Los Angeles, CA) are kynurenine mono-oxygenaseinhibitors for the potential treatment of HD (Thom-son Reuters Pharma, update of October 30, 2012). Thestructures were not communicated.

PF-04859989 (Pfizer, Fig. 14) is an inhibitor ofkynurenine (oxoglutarate) aminotransferase II for thepotential treatment of schizophrenia [586, 587] (Thom-son Reuters Pharma, update of May 8, 2013).

2.33. Drugs interacting with 5-lipoxygenase

The enzyme 5-lipoxygenase (5-LO) catalyzes theconversion of arachidonic acid to 5-hydroxy-peroxy-eicosatetraenoic acid (5-HPETE) and subsequently to5-hydroxy-eicosatetraenoic acid (5-HETE), which aremetabolized to different leukotrienes [588]. The influ-ence of 5-lipoxygenase on tau pathology was inves-tigated [589–591]. Gene knockout of 5-lipoxygenaserescued synaptic dysfunction and improved memoryin a triple-transgenic mouse model of AD [592–595].Also reduction of the 5-lipoxygenase activating pro-tein ameliorated cognitive deficits in a mouse model ofAD [596]. Mice receiving MK-591 (quiflapon, a FLAP,5-lipoxygenase-activating protein inhibitor) had a sig-nificant reduction of tau phosphorylation [597]. Therole of 5-lipoxygenase for DNA methylation was dis-cussed. The data were compiled in a recent review[598].

Minocycline (Wyeth, now Pfizer and Takedalaunched in 1999) is a second generation tetracyclinethat effectively crosses the BBB. It improved cogni-tive impairment in AD models [599]. It reduced thedevelopment of abnormal tau species in models of AD[600–602].

New classes of 5-lipoxygenase inhibitors were com-municated [603].

2.34. Drugs interacting with lysine-specifichistone demethylase 1

ORY-2001 (Oryzon Genomics, Barcelona) isa lysine specific demethylase-1 inhibitor for thepotential treatment of neurodegenerative disease(Thomson Reuters Pharma, update of May 19,2014). The structure was not communicated. Fora discussion on histone demethylation in patho-logical processes including neurodegeneration, see[604].

2.35. Drugs interacting with monoacylglycerollipase (MAGL)

Inactivation of MAGL, the primary enzyme metabo-lizing the endocannabinoid 2-arachidonoylglycerol inthe brain, by the highly selective and potent MAGLinhibitor JZL-184 (Fig. 14) [605, 606] robustly sup-pressed production and accumulation of BACE1 in amouse model of AD [607]. For a review on the topicmonoacylglycerol lipase as a therapeutic target for AD,see [608].


2.36. Drugs interacting with monoamine oxidase

Monoamine oxidase inhibitors: promising therapeu-tic agents for AD were described [609]. Recent effortsof medicinal chemists to explore ligands targetingMAOs were reviewed [610–612].

Ladostigil (TV-3326; Avraham Pharmaceuticals,Yavne, Israel under license from Yissum ResearchDevelopment, a wholly owned company of the HebrewUniversity of Jerusalem; see Fig. 5) is a dual acetyl-choline esterase and MAO inhibitor currently in PhaseII clinical trials in 190 patients in Europe since Decem-ber 2010. In February 2012, a Phase II trial wasinitiated in Israel and Europe in patients suffering fromMCI (Thomson Reuters Pharma, update of August 16,2013). See Chapter 2.1.1.9. Dual AChE and MAOinhibitors.

RG-1577 (RO-4602522; EVT-302; Roche, Basel,Switzerland and its Japanese subsidiary Chugai, Tokyounder license from Evotec, Hamburg) is an orallyactive, selective, and reversible MAO-B inhibitor. Thecompany initiated a Phase II trial in patients withAD in September 2012 (Thomson Reuters Pharma,update of April 25, 2014). The structure was notcommunicated.

HT-1067 (Dart NeuroScience LLC, San Diego, CApresumably under license from Helicon, San Diego,CA) is a reversible MAO-B inhibitor for the potentialmemory impairment in PD patients. In January 2013the drug entered Phase I development in the US for cog-nitive disorders (Thomson Reuters Pharma, update ofApril 10, 2014). The structure was not communicated.

HT-3951 (Dart NeuroScience LLC, San Diego, CA)is a potential backup compound for the reversibleMAO B inhibitor HT-1067 (Thomson Reuters Pharma,update of January 30, 2013). The structure was notcommunicated.

OG-45 (Oryzon Genomics, Barcelona) is a dualMAO-B inhibitor and lysine specific demethylase-1inhibitor (Thomson Reuters Pharma, update of April8, 2014). The structure was not communicated.

VAR-10200 (HLA-20; Varinel, West Chester, PA;Fig. 15) is a dual iron-chelating agent and MAO-Binhibitor for the potential treatment of age-related mac-ular degeneration [613] (Thomson Reuters Pharma,update of February 24, 2012).

VAR-10300 (M-30; Varinel, West Chester, PA,Technion, Haifa and the Weizmann Institute ofScience, Rehovot, Israel; Fig. 15) combines the iron-chelating properties of 8-hydroxy-quinoline with theMAO inhibitor moiety of rasaglinine [614] (ThomsonReuters Pharma, update of September 24, 2012).

Rasagiline (TVP-1012; (R)-enantiomer; Azilect,Agilect; marketed by Teva, Petach Tikva, Israel andLundbeck, Valby, DK; Fig. 15) proved to be a veryvaluable drug for the treatment of PD with sales in2012 of USD 330 million reported by Teva and USD211 million reported by Lundbeck. The effects ofrasagiline on cognitive deficits in cognitively-impairedPD patients were evaluated [615] (Thomson ReutersPharma, update May 5, 2014).

The Cleveland Clinic Foundation (Cleveland, OH)is investigating rasagiline for the potential treatment ofAD. In May 2014, a clinical trial was being planned(Thomson Reuters Pharma, update of June 5, 2014).

Tesa Labtec (Langenfeld, Germany), the ChongqingPharmaceutical Research Institute (Chongqing, China)and Teikoku Pharma (San Jose, CA) are independentlyevaluating sustained release transdermal patch formu-lations of rasagiline for the potential treatment of PD(Thomson Reuters Pharma, updates of March 15, 2013,of April 2, 2014, and of May 15, 2014, respectively).

Safinamide (FCE-26743; NM-1015, PNU-151774E; Zambon, Milano under license fromNewron, Milano, who acquired the rights fromPharmacia and Upjohn, now Pfizer; Fig. 15) is apotent MAO B inhibitor. Phase III trials in early PDpatients began in June 2004. An expert opinion onsafinamide in PD was published [616]. In December2013 the company submitted the MAA to the EMAas an add-on therapy to a stable dose of a singledopamine agonist or levodopa based on treatment ofmore than 2,000 PD patients treated over four years(Thomson Reuters Pharma, update of April 9, 2014).

Selegiline reversed A�25-35-induced cognitivedeficits in male mice [617].

2.37. Drugs interacting with myeloperoxidase

Torrey Pines Pharmaceuticals (Del Mar, CA)is investigating myeloperoxidase inhibitors for thepotential oral treatment of AD. Increased levelsof myeloperoxidase plasma levels were detected inpatients with AD [618] (Thomson Reuters Pharma,update January 29, 2014). Structures were notcommunicated.

2.38. Drugs interacting with neprilysin

Neprilysin (EC 3.4.24.11, NEP, neutral endopepti-dase, enkephalinase, neutrophil cluster-differentiationantigen 10 = CD10, common acute lymphoblasticleukemia antigen = CALLA) is a member of the zincmetalloproteinase family first discovered in the renal


Fig. 15. Four monoamine oxidase and three OGA inhibitors.

microvillar membrane in 1974 [619]. Cloning revealeda type II integral membrane protein of 749 amino acidresidues [620]. Neprilysin cleaves peptides smallerthan 5 kDa at the amino side of hydrophobic aminoacid residues including A�1-40 and A�1-42, which isthe longest substrate for neprilysin [621]. NEP can alsodegrade the oligomeric forms of A� [622]. Recombi-nant soluble neprilysin reduced A� accumulation andimproved memory impairment in AD mice [623].

Novartis scientists are investigating an Fc-neprilysin fusion protein for the potential treatmentof AD. The ED50 value of intravenous Fc-neprilysinwas 8.5 mg/kg. In vivo, Fc-neprilysin (630 nM i.v.)degraded A�. In plaque bearing A�PP23 mice,chronic peripheral dosing of Fc-neprilysin (100 mg/kgq12d to q16d) did not reduce brain A� levels.Significant reductions in plasma A�1-40 levels wereobserved with Fc-neprilysin [624] (Thomson ReutersPharma update of November 27, 2013).

2.39. Drugs modulating O-linkedN-Acetylglucosaminidase (O-GlcNAcase;OGA)

O-GlcNAc and neurodegeneration, its biochemicalmechanisms and potential roles in AD and beyond

were described [625]. The tau O-GlcNAcylation andphosphorylation sites in mouse brain synaptosomeswere elucidated [626]. O-GlcNAc may compete withphosphorylation of the same serine or threonineresidues. O-GlcNAc levels may directly influence neu-rodegenerative disease progression [627]. A dynamicview to the modulation of phosphorylation andO-GlcNAcylation was described [628]. IncreasedO-GlcNAcylation reduced pathological tau withoutaffectiong its normal phosphorylation in a mousemodel of tauopathy [629]. O-GlcNAc modification oftau directly inhibited its aggregation without perturb-ing the conformational properties of tau monomers[630]. A comparison of the anti-amyloidogeniceffects of O-mannosylation, O-galactosylation, and O-GalNAc glycosylation was presented [631].

Alectos Therapeutics (Burnaby, BC) in col-laboration with Merck is investigating O-linkedN-acetyl-glucosaminidase (O-GlcNAcase) modula-tors (Thomson Reuters Pharma update of May 30,2014).

ASN-61 and ASN-461 (Asceneuron, Lausanne,Switzerland) are small molecule inhibitors of O-GlcNAcase for the potential treatment of AD. In amouse model of tau aggregation, ASN-61 (30 mg/kgpo, qdx5) increased tau O-GlcNAcylation in a robust


manner. In vivo ASN-461 demonstrated a minimaleffective dose below 1 mg/kg and at 10 mg/kg thein vivo response was greater than that for ThiametG (500 mg/kg). At doses between 1- and 10-mg/kgASN-461, total brain protein O-GlcNAcylation wassignificantly greater than that for the vehicle (Thom-son Reuters Pharma update of March 25, 2014). Thestructures were not communicated.

GlcNAcstatin (University of Dundee; Fig. 15) isa rationally designed glucoimidazole, which inhib-ited bacterial OGA (bOGA) with a Ki of 4.6 pM forthe potential treatment of AD [632, 633] (ThomsonReuters Pharma, update of October 26, 2012).

NButGT (Seoul National University; Fig. 15) isa specific inhibitor of O-GlcNAcase, which reducedA� production by lowering �-secretase activity bothin vitro and in vivo. O-GlcNAcylation takes place atthe S708 residue of nicastrin [634]. NButGT atten-uated A� plaques and rescued memory impairmentin 5xFAD mice. The synthesis was described bychemists of the Simon Fraser University (Burnaby, BC)[635].

SEG-4 (Summit Corporation, Abington, UK) inhib-ited OGA with IC50 and Ki values of 10 and 72 nM,respectively. The compound significantly reducedtau phosphorylation (Thomson Reuters Pharma,update of April 9, 2014). The structure was notcommunicated.

Thiamet-G (Simon Fraser University, Burnaby, BC;Fig. 15) is a potent inhibitor of human O-GlcNAcase(Ki = 21 nM) and efficiently reduced phosphorylationof tau at Thr231, Ser396, and Ser422 in both rat cor-tex and hippocampus [636]. For a commentary, see[637]. Acute thiamet G treatment led to a decreasein tau phosphorylation at Thr181, Thr212, Ser214,Ser262/Ser356, Ser404, and Ser409 and an increasein tau phosphorylation at Ser199, Ser202, Ser396, andSer422 in mouse brain, probably via stimulation ofGSK-3� activity [638].

2.40. Drugs interacting with peptidyl-prolylcis-trans isomerase D

Peptidyl-prolyl isomerase activity of FK506 bind-ing protein 12 prevented tau peptide from aggregating[639].

Scynexis (Research Triangle Park, NC) was inves-tigating a series of cycophilin D inhibitors forthe potential treatment of muscle injury, ischemia,reperfusion injury, trauma, and neurodegenerative dis-ease. The program was terminated (Thomson ReutersPharma, update of January 2, 2013).

2.41. Drugs interacting with phosphodiesterases

Several excellent reviews on PDE inhibition andcognition enhancement were published [640–642]. Areview on phosphodiesterases as therapeutic targets forAD was communicated [643]. Based on the expressionof PDE mRNA in the human brain, it was suggestedthat PDE1 and PDE10 inhibitors are strong candidatesfor the development of cognition enhancers. ChronicPDE 2 inhibition with BAY60-7550 improved memoryin the A�PPswe/PS1dE9 mouse model of AD [644].Knockdown of the long-form of phosphodiesterase-4D (PDE4D) reversed A�42-induced memory deficitsin mice [645]. The medicinal chemistry of PDE 4inhibitors [646], of PDE5 inhibitors [647], and ofPDE10A inhibitors was reviewed [648].

HT-0712 (IPL-455903; Dart Neuroscience, SanDiego, CA presumably under license from Helicon,San Diego, CA, under license from Orexo, formerlyBiolipox, Uppsala, Sweden; Fig. 16) is a PDE4inhibitor for the potential treatment of memory disor-ders [649, 650]. In January 2013 the drug was listed asbeing in Phase II development for cognitive disorders(Thomson Reuters Pharma, update of April 9, 2014).

OMS-824 (Omeros, Seattle, WA; Fig. 16) isa PDE10 inhibitor for the potential treatment ofschizophrenia in Phase II clinical trials since Septem-ber 2013. The trial enrolled 33 patients. Data werereported in January 2014 showing that OMS-824 waswell tolerated and tolerability and pharmacokineticswere not affected by concomitant antipsychotic medi-cations. Omeros initiated a Phase II trial of OMS-824for HD [651] (Thomson Reuters Pharma, update ofJune 5, 2014).

PF-02545920 (MP-10; Pfizer; Fig. 16) is a PDE10Ainhibitor in a randomized, double-blind, placebo-controlled Phase II clinical trial in patients with acuteschizophrenia (n = 260) since October 2010. Develop-ment for the indication schizophrenia was terminated.PF-02545920 is now evaluated in a Phase II clinicaltrial in France for the oral treatment of HD since Octo-ber 2013 [652] (Thomson Reuters Pharma, update ofJune 4, 2014).

AVE-8112 (Aventis, now sanofi and The Michael J.Fox Foundation, New York, NY) is a PDE4 inhibitorfor the potential treatment of PD. In January 2013a multiple ascending dose, safety and efficacy PhaseI study was initiated in patients with PD (expectedn = 32) (Thomson Reuters Pharma, update of March8, 2013). The structure was not communicated.

ITI-214 (Takeda, Osaka under license of Intra-Cellular Therapies, New York, NY; Fig. 16) is a PDE1


Fig. 16. Eleven phosphodiesterase and one phospholipase A2 inhibitor(s).


inhibitor for the potential oral treatment of cognitivedisorders associated with schizophrenia. In February2013 a randomized, double-blind, placebo-controlled,pharmacokinetic single rise dose Phase I trial was com-pleted in healthy subjects (n = 70). Results showed thatthe drug was safe and well tolerated with a favorablepharmacokinetic profile consistent with once-a-daydosing [653, 654] (Thomson Reuters Pharma, updateof April 8, 2014).

Lu-AF11167 (Lundbeck, Valby, DK) is an inhibitorof a brain-expressed PDE enzyme for the potentialtreatment of AD, HD, and schizophrenia in a PhaseI clinical trial since March 2011 (Thomson ReutersPharma, update of November 15, 2013). The structurewas not communicated.

18F-PF-05270430 (Pfizer and Yale University, NewHaven, CT as part of the Yale-Pfizer BioimagingResearch Alliance, Fig. 16) is a PDE2A-selective CNSPET ligand for the potential diagnosis of AD [655].By June 2013 Phase I studies were ongoing in sixhealthy male volunteers. Tracer uptake was the highestin the striatum, followed by neocortices and cerebel-lum (Thomson Reuters Pharma, update of December3, 2013).

RG-7203 (RO-5545965; Roche) is a PDE10Ainhibitor for the potential treatment of schizophrenia.In October 2012 a Phase I trial began in the Netherlandsin healthy subjects (n = 92). The study was completedin March 2013 (Thomson Reuters Pharma, update ofJanuary 30, 2014). The structure was not communi-cated.

There are several PDE inhibitors in preclinical eval-uation (in alphabetical order):

AB-03 (Araclon Biotech, Zaragoza) is a hetero-cyclic PDE7 inhibitor for the potential treatment ofPD (Thomson Reuters Pharma, update of March 17,2014). The structure was not disclosed.

AMG-7980 (Amgen, Thousand Oaks, CA in col-laboration with Envoy Therapeutics, Jupiter, FL andColumbia University, New York, NY; Fig. 16) is anovel PDE10A inhibitor with a Ki of 0.94 nM usefulas tritiated or PET ligand to measure PDE10A tar-get occupancy in brain [656–660] (Thomson ReutersPharma, update of October 13, 2013).

BCR-159 (BCA-159; BioCrea, Radebeul, Ger-many; Fig. 16) is a PDE 10 inhibitor for thepotential treatment of schizophrenia and HD [652](Thomson Reuters Pharma, update of November 22,2013).

Cilostazol (Otsuka, Tokyo; launched in 1993), aselective PDE3 inhibitor, protected against A�1-40-induced suppression of viability and neurite elongation

[661]. It also attenuated A�-induced tauopathy viaactivation of CK2�/SIRT1 [662].

CPL-204-015 (Celon Pharma, Lomianki, Poland) isa phosphodiesterase 9A (PDE9A) inhibitor and cog-nition enhancer for the potential treatment of AD(Thomson Reuters Pharma, update of January 6, 2014).The structure was not communicated.

DG-071 (Tetra Discovery Partners, Grand Rapids,MI) is a PDE4b inhibitor for the potential treatment ofdepression (Thomson Reuters Pharma, update of May5, 2014). The structure was not communicated.

Icariin, a flavonoid isolated from Epimedii herba,is a phosphodiesterase-5 inhibitor. It inhibited A�25-35induced expression of BACE in rat hippocampus [663]and attenuated A�-induced neurotoxicity by inhibi-tion of tau protein hyperphosphorylation in PC12cells [664]. It attenuated lipopolysaccharide-inducedmicroglial activation and resultant death of neuronsby inhibiting TAK1/IKK/NF-κB and JNK/p38 MAPKpathways [665]. It improved memory impairment inAD model mice and attenuated A�-induced neuriteatrophy [666] and learning and memory in A�PP/PS1transgenic mice by stimulating NO/cGMP signal-ing [667]. There seems to be a synergistic effectto improve learning and memory deficits in rats byco-administration of Icariin and Panax notoginsengsaponins [668].

OMS-527 (Omeros, Seattle, WA licensed fromAsubio Pharma, Kobe, a part of Daiichi Sankyo,Tokyo) is a PDE-7 inhibitor investigated for the poten-tial treatment of addiction, compulsive disorder andneurological disorders, including PD, restless legs syn-drome, and movement disorders (Thomson ReutersPharma, update of November 11, 2013). The structurewas not communicated.

PDE-4D inhibitors (Tetra Discovery Partners,Grand Rapids, MI) are evaluated for the potential treat-ment of AD and associated MCI (Thomson ReutersPharma, update of March 8, 2014) Structures were notcommunicated.

PDE-9 inhibitor (Lundbeck, Valby, DK; Fig. 16)is investigated for the potential treatment ofAD. The compound showed a high potency atPDE-9 (IC50 = 28 nM), good selectivity (PDE-1:IC50 = 240 nM) and a good ADME profile in rats [669](Thomson Reuters Pharma, update of October 28,2013).

PDE-9A inhibitor (Pfizer; Fig. 16) for the poten-tial treatment of AD exhibited an IC50 of 32 nMfor PDE9A, was 30 fold selective over PDE1C anddisplayed a brain/plasma ratio of 1.4 in rat [670](Thomson Reuters Pharma, update of April 22, 2013).


PF-999 (Pfizer, Fig. 16) is a PDE2A inhibitor forthe potential treatment of cognitive impairment associ-ated with schizophrenia [671, 672] (Thomson ReutersPharma, update of September 6, 2012).

Roflumilast (Daxas; Takeda Pharmaceuticals Inter-national, Opfikon, Switzerland, previously Nycomed),a PDE4 inhibitor launched in 2010, and donepezil areclinically evaluated to reverse scopolamine inducedcognitive deficits in healthy adults (NCT02051335).Sales for roflumilast reported by Takeda for 2012 wereUSD 37.5 million (Thomson Reuters Pharma, updateof April 18, 2014).

S14, an inhibitor of PDE7, reduced cognitive impair-ment and pathological hallmarks in a mouse model ofAD [673].

Sildenafil (Viagra, Pfizer, launched in 1998) andTadalafil (Cialis, Lilly, launched in 2003), potentPDE5 inhibitors, restored cognitive function withoutaffecting A� burden in a mouse model of AD [674].Tadalafil reversed cognitive dysfunction in a mousemodel of AD [675–677].

THPP-1 (Merck, Fig. 16) is a potent, orally bioavail-able PDE10A inhibitor, which improved episodic-likememory in rats and executive function in Rhesusmonkeys [678] (Thomson Reuters Pharma, update ofFebruary 22, 2013).

VP1.15 (CSIC, Madrid and University of Toronto,see Fig. 12) is a dual GSK-3 and PDE7 inhibitoracting as an antipsychotic and cognitive enhancer inC57BL/6J mice [469]. See also Chapter 2.24. Drugsinteracting with GSK-3�.

The development of several PDE inhibitors wasterminated: of BCA-909 (BCR-909; Boehringer Ingel-heim under license from BioCrea), dual PDE10/PDE 2 inhibitors (biocrea), etazolate (EHT-202;SQ-20009; also an �-secretase activator; Diaxon-hit, formerly Exonhit), GEBR-7b (University ofGenoa; [679, 680]), PDE 2 inhibitors (BioCrea) andPF-03049423 (a PDE5 inhibitor, Pfizer).

2.42. Drugs interacting with phospholipase A2and D2

The role of secretory phospholipase A2 in the cen-tral nervous system and in neurological diseases wasdescribed [681]. Inhibition of phospholipase A2 in ratbrain decreased the levels of total tau protein [682].

Rilapladib (SB-659032; GSK using a technologylicensed from Human Genome Sciences, Rockville,MD; Fig. 16) is a lipoprotein-associated phospholipaseA2 (LP-PLA2) inhibitor for the potential oral treatmentof atherosclerosis and AD. In October 2011 a random-

ized, double-blind, placebo-controlled Phase II studywas initiated in 120 AD patients with evidence of car-diovascular disease in Europe [683] (Thomson ReutersPharma, update of May 6, 2014).

GSK-2647544 (GSK) is a lipoprotein-associatedphospholipase A2 inhibitor for the potential treatmentof AD in Phase I clinical trials since November 2012in Australia. In December 2013 another Phase I trialwas initiated in the UK (Thomson Reuters Pharma,update of April 17, 2014). The structure was notcommunicated.

Darapladib (GSK) reduced accumulation of A�42in neurons [684]. The drug is in Phase III for the treat-ment of atherosclerosis for the potential oral preventionof cardiovascular events in patients with atherosclero-sis and coronary artery disease since 2008 (ThomsonReuters Pharma, update of January 22, 2014).

The development of icosapent ethyl (AMR-101, SC-111, LAX-101; MND-21; Epadel; ethyl-eicosapentaenoic acid; Mochida Pharmaceutical Co.,Tokyo and Amarin, Dublin, Ireland under license fromScotia Holdings, Guildford, Surrey, UK), a phospho-lipase A2 inhibitor, in the indication age-associatedmemory impairment was discontinued (ThomsonReuters Pharma, update of May 6, 2014).

2.43. Drugs interacting with plasminogenactivator inhibitor (PAI)

Tissue plasminogen activator could degrade A�molecules resulting in a delay of AD pathogenesis[685]. Elevated serum PA1-1 was associated witha high risk for cognitive dysfunction [686]. PAI-1 promoted synaptogenesis and protected againstA�1-42-induced neurotoxicity [687].

2.44. Drugs interacting with Poly ADP-Ribosepolymerase (PARP)

E-7016 (Eisai, Tokyo following the acquisition ofMGI Pharma, Bloomington, MN, formerly Guilford,Baltimore, MD; presumed to be GPI-21016 underlicense from Johns Hopkins University, Baltimore,MD, Fig. 17) is an orally active, brain-penetrable,PARP PAR synthase inhibitor in Phase II clinical tri-als for the treatment of stage III/IV melanoma patients[688]. The indications AD and stroke were abandoned(Thomson Reuters Pharma, update of May 14, 2014).

MP-124 (Mitsubishi Tanabe Pharma, Osaka) ina PARP inhibitor for the potential treatment ofacute ischemic stroke in Phase I clinical trials sinceDecember 2008 in the US and since January 2011 in


Fig. 17. A poly ADP-ribose polymerase inhibitor, prostaglandin D and E modulators and a protein kinase C ε activator.

Canada (Thomson Reuters Pharma, update of February3, 2014). The structure was not communicated.

The development of AL-309 (Allon Therapeutics,Vancouver, BC), a neuroprotective peptide and PARPstimulator, was suspended.

2.45. Drugs interacting with human presequenceprotease

Human Presequence Protease (hPreP) is responsi-ble for the degradation of mitochondrial A� peptide inhuman neuronal cells, and is thus an attractive targetto increase the proteolysis of A�. Therefore, it offersa potential target for AD drug design, by identifyingpotential activators of hPreP. Medicinal chemists ofthe University of Kansas applied structure-based drugdesign combined with experimental methodologies toinvestigate the ability of various compounds to enhancehPreP proteolytic activity. Small benzimidazolederivatives (Compound 3c is shown in Fig. 17) mayprovide a promising avenue for AD treatment [689].

2.46. Drugs interacting with prolyl endo peptidase

Prolyl oligopeptidase colocalizes with �-synuclein,A�, tau protein and astroglia in the postmortem brainsamples with PD and AD [690]. Inhibitors of prolyloligopeptidase showed a significant antiaggregationeffect on �-synuclein [691].

At present there is no drug in clinical or preclinicaldevelopment.

2.47. Drugs interacting with prostaglandin D & Esynthases

Microsomal prostaglandin E synthase-1 is inducedin AD [692].

HF-0220 (7�-hydroxy-epiandrosterone; NewronPharmaceuticals, Milano; Fig. 17) is a cytoprotectivesteroid, which stimulated prostaglandin D synthasefor the potential treatment of AD. A Phase IIa mul-ticenter, double-blind, placebo-controlled, biomarkertrial in AD patients was initiated in April 2007. HF-0220 was well tolerated at all doses (Thomson ReutersPharma, update of June 24, 2013).

AAD-2004 (GNT Pharma, Yongin, South Korea,formerly Neurotech and US subsidiary AmKor;Fig. 17) is a prostaglandin E synthase-1 inhibitor forthe treatment of AD, PD, and ALS. A Phase I study wasinitiated in April 2010. By December 2011 the singleascending dose trial was successfully completed [693](Thomson Reuters Pharma, update of May 7, 2014).

2.48. Drugs interacting with protein kinase C(PKC)

APH-0703 (Aphios, Woburn, MA), a potentPKC activator and a nanoparticle formulation


Fig. 18. A Rho GTPase and two sirtuin-1 modulator(s) and two transglutaminase 2 inhibitors.

of bryostatin-1 and formulated using Aphios’shydrophobic-based and SFS-PNS polymernanospheres technologies, is in Phase II clinicaltrials since May 2010. The development of the i.v.formulation was taken into Phase III clinical trialsin September 2013 in the US. An oral nanoparticleformulation is in preclinical evaluation (ThomsonReuters Pharma, updates of June 6, 2014 for both).

Bryostatin-1 (Neurotrope BioScience, Plantation,FL in collaboration with the Blanchette RockefellerNeurosciences Institute, Morgantown, WV) is a nat-urally occurring PKC activator isolated from theCalifornian marine bryozoan Bugula neritina. In April2014 the program was listed as being in Phase IIadevelopment for familial AD, clinical developmentfor fragile X syndrome and in lead optimization forischemic stroke and traumatic brain injury. Bryostatin-1 improved survival and reduced ischemic brain injuryin aged rats after acute ischemic stroke (ThomsonReuters Pharma, update of June 5, 2014). See alsoChapter 2.3. Drugs interacting with �-secretase.

DCP-LA, DHA-CP6 and BR-111 (NeurotropeBioScience, Plantation, FL in collaboration withthe Blanchette Rockefeller Neurosciences Institute,Morgantown, WV) are lipophilic PKC epsilon acti-vators, back-up compounds of bryostatin-1, forthe potential treatment of AD. In April 2014 theprogram was listed as being in Phase I develop-ment (Thomson Reuters Pharma, update of June 6,2014).

�,�-DCP-LA (Hyogo College of Medicine, Japan;Fig. 17) is an activator of PKCε for the potentialtreatment of stroke and cognitive disorder (ThomsonReuters Pharma, update of January 2, 2014).

Aplysiatoxin derivatives (Kyoto University),which bind to protein kinase C isozymes, showedhigh cytostatic and antiproliferative activity whencompared to bryostatin-1 [694–696] (ThomsonReuters Pharma, update of October 29, 2013).

A dual PKC activator and HDAC inhibitor thatdecreases A� production is currently evaluated by sci-entists of the University of Illinois at Chicago for thepotential treatment of AD (Thomson Reuters Pharma,update of November 4, 2013). The precise structurewas not communicated. It is a modified benzolactamcompound.

Genistein, the most active molecule of soyisoflavones, inhibited A�25-35-induced neurotoxicityin PC12 cells via a PKC signaling pathway [697].

The development of PKC modulators (GeorgetownUniversity Medical Center, Washington, DC and Neu-rologic, Rockville, MD) was terminated.

2.49. Drugs interacting with protein phosphataseslingshot homolog 2

University of California San Diego researchersare investigating slingshot-2 inhibitors for the poten-tial treatment of cancer and AD (Thomson ReutersPharma, update of June 11, 2013).


2.50. Drugs interacting with protein tyrosinephosphatase

Knockout mice revealed a role for protein tyrosinephosphatase in cognition [698].

2.51. Drugs interacting with Rac1 GTPase

The development of Sanquinarinium chloride(Diaxonhit, formerly ExonHit) was discontinued.

2.52. Drugs interacting with ras farnesyltransferase

LNK-754 (OSI-754, CP-609754; AstraZenecafollowing the acquisition of Link Medicine’s neuro-science assets under license from OSI Pharmaceuti-cals, a subsidiary of Astellas Pharma, and Pfizer) wasan orally active inhibitor of ras farnesyl transferase.Treatment of transgenic mice at 6 months of age for 3months showed a clear reduction of plaques caused byeither �-synuclein or A� [699]. The development wasterminated (Thomson Reuters Pharma, update of June26, 2013).

2.53. Drugs interacting with Rho GTPase

ZCL-278 (East Carolina University, Greenville,NC; Fig. 18) is a small molecule targeting CDC42Rho GTPase signaling for the potential treatment ofAD [700] (Thomson Reuters Pharma, update of July29, 2013).

2.54. Drugs interacting withS-adenosylhomocysteine hydrolase

The development of L-002259713 (Merck) wasterminated.

2.55. Drugs interacting serine palmitoyltransferase

Serine palmitoyltransferase is upregulated in a sub-group of sporadic AD patient brains [701]. Inhibitionof serine palmitoyltransferase by subcutaneous L-cycloserine reduced A� and tau hyperphosphorylationin an AD mouse model (TgCRND8). This may be asafe strategy for the treatment of AD [702].

2.56. Drugs interacting with sirtuin

The class III histone deacetylases, sirtuins 1–7, andthe sirtuin activating compounds were reviewed [703].

Reviews on sirtuins in neurodegenerative diseases[704] and in brain aging [705, 706] were published.There are distinct patterns of sirtuin expression duringthe progression of AD [739].

Resveratrol (Fig. 18) is a natural phyto com-pound, which activates Sirtuin-1 and reduced A�accumulation. It attenuated cerebral ventricularstreptotocin-induced tau hyperphosphorylation [707].Resveratrol-fed mice demonstrated increases in GSK-3� phosphorylation and a 3.8-fold increase oftransthyretin [708]. Dietary resveratrol prevented ADin SAMP8 mice [709].

The Georgetown University Medical Center, Wash-ington, DC, started at Phase II, randomized,double-blind, placebo-controlled study in patients withmild to moderate AD (expected n = 120) in the US inMay 2012 (Thomson Reuters Pharma, update of June22, 2012).

In order to improve on the unfavorable pharma-cokinetics resveratrol-loaded lipid-core nanocapsules(RSV-LNC) were generated. Pre- and co-treatmentswith RSV-LNC were able to protect cultures againstreactive oxygen species formation and cell deathinduced by A�, possibly through sustained blockingof TNF�, IL1�, and IL-6 release. Furthermore, RSV-LNC was able to increase IL-10 release even in thepresence of A� and prevent or decrease both glial andJNK activation [710].

Resveratrol derivatives were explored as A�1-42aggregation inhibitors, antioxidants, and neuroprotec-tive agents [711, 712] (Thomson Reuters Pharma,update of March 6, 2014).

Selisistat (SEN-196, EX-527, SEN-0014196; SienaBiotech under license from Elixir Pharmaceuticals,Cambridge, MA; Fig. 18) is a Sirtuin-1 inhibitor. InNovember 2011 a randomized, double-blind, PhaseII trial was initiated to study the safety and tolera-bility of selisistat administered over 12 weeks in HDpatients (n = 144). The trial was completed in October2012. Selisistat is a racemic compound [715] (Thom-son Reuters Pharma, update of April 9, 2014).

Curcumin via activation of SIRT1 blocked the neu-rotoxicity of amyloid-�25-35 in rat cortical neurons[740].

INDUS-815C (Indus Biotech, Pune, India) is a natu-ral NAD-dependent deacetylase Sirtuin-2 inhibitor forthe potential treatment of HD. The drug was also eval-uated for the potential treatment of age-related maculardegeneration and retinopathy, but this indication wasabandoned (Thomson Reuters Pharma, updates of Jan-uary 29, 2014 and January 28, 2014, respectively). Thestructure was not communicated.


2.57. Drugs interacting with steroid sulfatase

Steroid sulfatase is a potential modifier of cognitionin ADHD [716].

2.58. Drugs interacting with synaptojanin 1

Synaptojanin 1 (Synj1), a lipid phosphatase medi-ating the breakdown of PI (4,5)P2, has been shownto play a role in synaptic vesicle recycling and recep-tor trafficking in neurons. Heterozygous deletion ofSynj1 protected neurons from A�-induced synapticloss and restored learning and memory in a mousemodel of AD [717]. Thus, inhibition of Synj1 may ame-liorate A�-associated impairments, suggesting Synj1as a potential therapeutic target. A screening assayfor Synj1 based on detection of inorganic phosphateliberation from a water-soluble, short-chain PI(4,5)P2was developed. The assay displayed saturable kineticsand detected Synj1’s substrate preference for PI(4,5)P2over PI(3,4,5)P3. The assay will enable identificationof novel Synj1 inhibitors that have potential utility aschemical probes to dissect the cellular role of Synj1 aswell as potential to prevent or reverse AD-associatedsynaptic abnormalities [718, 719].

2.59. Drugs interacting with transglutaminase(TG2)

Tissue transglutaminase catalyzes protein cross-linking, an important molecular process in AD. Itsinvolvement in the pathogenesis and its potential as atherapeutic target was reviewed recently [720]. Tissuetransaminase may also serve as a biochemical markerfor AD [721].

CHDI-00339864 and CHDI-00316226 (Evotec;Hamburg, in collaboration with the CHDI Founda-tion; Los Angeles, CA; Fig. 18) are selective TG2inhibitors (IC50 = 7 nM for TG2 for CHDI-00316226)for the potential treatment of HD. It displayed an 85fold greater selectivity for TG2 over Factor XIIIA[722] (Thomson Reuters Pharma, update of October30, 2012).

2.60. Drugs interacting with ubiquitincarboxyl-terminal hydroxylase (Usp14)

Usp14 inhibitors (Proteostasis Therapeutics, Cam-bridge, MA in collaboration with Biogen Idec, Weston,MA under license from Harvard University, Cam-bridge, MA) are investigated for the potential treatmentof neurodegenerative diseases (Thomson Reuters

Pharma, update of March 3, 2014). Structures werenot communicated.

3. CONCLUSION

With the launch of donepezil (Aricept) in 1996,rivastigmine (Exelon) in 2000, and galantamine(Reminyl) in 2001 (inhibitors of acetyl and butyrylcholinesterase), three valuable medications are avail-able for the treatment of patients with mild to moderateAD. Huperzine A was launched in China in 1995, butthe four times a day administration makes it less attrac-tive, a problem which may be solved by the transdermalpatch XEL-001HP.

So far, the development of 11 Phase III compoundsinteracting with enzymes for the potential treatmentof AD was discontinued, i.e., of the AChE inhibitorsamiridin, eptastigmine, metrifonate, phenserine, andvelnacrine, of the �-secretase inhibitors begacestat andsemagacestat, the �-secretase modulator tarenflurbil,the MAO inhibitors rasagiline and safinamide, and thePDE inhibitor propentofylline.

Three compounds interacting with enzymes arecurrently in Phase III clinical trials for the poten-tial treatment of AD: MK-8931, a BACE inhibitor;masitinib, an inhibitor of c-kit; Lyn and PDGF-R kinases; and APH-0703, a protein kinase Cactivator.

There are currently 16 compounds interacting withenzymes in Phase II clinical trials for the potentialtreatment of AD: posiphen, Shen Er Yang, and XEL-001HP (AChE inhibitors), ladostigil (dual AChEand MAO inhibitor), CHF-5074 and EVP-0962 (�-secretase modulators), FRM-0334 (HDAC inhibitor),RG-1577 (MAO B inhibitor), HT-0712, OMS-824,PF-02545920, and PF-03049423 (phosphodiesteraseinhibitors), rilapladib (phospholipase A2 inhibitor),HF-0220 (prostaglandin D synthase stimulator), andresveratrol and selisistat (sirtuin-1 modulators).

It may be that positive results will be obtained fromthe three Phase III trials within the next two to threeyears.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://www.j-alz.com/disclosures/view.php?id=2236).

REFERENCES

[1] Giurgea C (1972) [Pharmacology of integrative activ-ity of the brain. Attempt at nootropic concept in

http://www.j-alz.com/disclosures/view.php?id=2236


psychopharmacology]. Actual Pharmacol (Paris) 25,115-156.

[2] Giurgea C (1973) The “nootropic” approach to the pharma-cology of the integrative activity of the brain. Cond Reflex8, 108-115.

[3] Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clay-ton NS, Connor R, Davis S, Deakin B, DeRubeis RJ, DuboisB, Geyer MA, Goodwin GM, Gorwood P, Jay TM, JoelsM, Mansuy IM, Meyer-Lindenberg A, Murphy D, Rolls E,Saletu B, Spedding M, Sweeney J, Whittington M, YoungLJ (2012) Cognitive dysfunction in psychiatric disorders:characteristics, causes and the quest for improved therapy.Nat Rev Drug Discov 11, 141-168.

[4] Froestl W, Maitre L (1989) The families of cognitionenhancers. Pharmacopsychiatry 22(Suppl 2), 54-100.

[5] Froestl W, Muhs A, Pfeifer A (2012) Cognitive enhancers(nootropics). Part 1: Drugs interacting with receptors.J Alzheimers Dis 32, 793-887.

[6] Froestl W, Muhs A, Pfeifer A (2013) Cognitive enhancers(nootropics). Part 2: Drugs interacting with enzymes.J Alzheimers Dis 33, 547-658.

[7] Froestl W, Pfeifer A, Muhs A (2013) Cognitive enhancers(nootropics). Part 3: Drugs interacting with targets otherthan receptors or enzymes. Disease-modifying drugs.J Alzheimers Dis 34, 1-114.

[8] Bartus RT, Dean RL III, Beer B, Lippa AS (1982) Thecholinergic hypothesis of geriatric memory dysfunction.Science 217, 408-414.

[9] Anand P, Singh B (2013) A review on cholinesteraseinhibitors for Alzheimer’s disease. Arch Pharm Res 36, 375-399.

[10] Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, SinghD (2013) Acetylcholinesterase inhibitors as Alzheimer ther-apy: From nerve toxins to neuroprotection. Eur J Med Chem70C, 165-188.

[11] Colombres M, Sagal JP, Inestrosa NC (2004) An overviewof the current and novel drugs for Alzheimer’s disease withparticular reference to anti-cholinesterase compounds. CurrPharm Des 10, 3121-3130.

[12] Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K (1995)Synthesis and structure-activity relationships of acetyl-cholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and relatedcompounds. J Med Chem 38, 4821-4829.

[13] Kryger G, Silman I, Sussman JL (1998) Three-dimensionalstructure of a complex of E2020 with acetylcholinesterasefrom Torpedo californica. J Physiol Paris 92, 191-194.

[14] Grutzendler J, Morris JC (2001) Cholinesterase inhibitorsfor Alzheimer’s disease. Drugs 61, 41-52.

[15] Cheewakriengkrai L, Gauthier S (2013) A 10-year per-spective on donepezil. Expert Opin Pharmacother 14, 331-338.

[16] Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M(2013) A meta-analysis of the efficacy of donepezil, rivastig-mine, galantamine, and memantine in relation to severity ofAlzheimer’s disease. J Alzheimers Dis 35, 349-361.

[17] Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C,Jiang T, Zhu XC, Tan L (2014) Efficacy and safety ofdonepezil, galantamine, rivastigmine, and memantine for thetreatment of Alzheimer’s disease: A systematic review andmeta-analysis. J Alzheimers Dis 41, 615-631.

[18] Berk C, Sabbagh M (2012) Broader considerations of higherdoses of donepezil in the treatment of mild, moderate, andsevere Alzheimer’s disease. Int J Alzheimers Dis 2012,707468.

[19] Schwartz LM, Woloshin S (2012) How the FDA forgotthe evidence: The case of donepezil 23mg. BMJ 344,e1086.

[20] Christensen DD (2012) Higher-dose (23mg/day) donepezilformulation for the treatment of patients with moderate-to-severe Alzheimer’s disease. Postgrad Med 124, 110-116.

[21] Darreh-Shori T, Soininen H (2010) Effects of cholinesteraseinhibitors on the activities and protein levels ofcholinesterases in the cerebrospinal fluid of patients withAlzheimer’s disease: A review of recent clinical studies.Curr Alzheimer Res 7, 67-73.

[22] Li DQ, Zhou YP, Yang H (2012) Donepezil combined withnatural hirudin improves the clinical symptoms of patientswith mild-to-moderate Alzheimer’s disease: A 20-weekopen-label pilot study. Int J Med Sci 9, 248-255.

[23] Gauthier S, Molinuevo JL (2013) Benefits of com-bined cholinesterase inhibitor and memantine treatment inmoderate-severe Alzheimer’s disease. Alzheimers Dement9, 326-331.

[24] Gareri P, Putignano D, Castagna A, Cotroneo AM, DePG, Fabbo A, Forgione L, Giacummo A, Lacava R,Marino S, Simone M, Zurlo A, Putignano S (2014) Ret-rospective study on the benefits of combined Memantineand cholinEsterase inhibitor treatMent in AGEd patientsaffected with Alzheimer’s disease: The MEMAGE study.J Alzheimers Dis 41, 633-640.

[25] Dubois B, Tolosa E, Katzenschlager R, Emre M, Lees AJ,Schumann G, Pourcher E, Gray J, Thomas G, Swartz J,Hsu T, Moline ML (2012) Donepezil in Parkinson’s diseasedementia: A randomized, double-blind efficacy and safetystudy. Mov Disord 27, 1230-1238.

[26] Krupp LB, Christodoulou C, Melville P, Scherl WF, PaiLY, Muenz LR, He D, Benedict RH, Goodman A, Rizvi S,Schwid SR, Weinstock-Guttman B, Westervelt HJ, WishartH (2011) Multicenter randomized clinical trial of donepezilfor memory impairment in multiple sclerosis. Neurology 76,1500-1507.

[27] Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDon-ald S, Gergel I (2004) Memantine treatment in patientswith moderate to severe Alzheimer disease already receiv-ing donepezil: A randomized controlled trial. JAMA 291,317-324.

[28] Chitnis S, Rao J (2009) Rivastigmine in Parkinson’s diseasedementia. Expert Opin Drug Metab Toxicol 5, 941-955.

[29] Wesnes KA, McKeith IG, Ferrara R, Emre M, del ST,Spano PF, Cicin-Sain A, Anand R, Spiegel R (2002) Effectsof rivastigmine on cognitive function in dementia withlewy bodies: A randomised placebo-controlled internationalstudy using the cognitive drug research computerised assess-ment system. Dement Geriatr Cogn Disord 13, 183-192.

[30] Vincent S, Lane R (2003) Rivastigmine in vascular demen-tia. Int Psychogeriatr 15(Suppl 1), 201-205.

[31] Moretti R, Torre P, Antonello RM, Cazzato G, Bava A (2004)Rivastigmine in vascular dementia. Expert Opin Pharma-cother 5, 1399-1410.

[32] Craig D, Birks J (2005) Rivastigmine for vascular cognitiveimpairment. Cochrane Database Syst Rev, CD004744.

[33] Roman GC (2005) Rivastigmine for subcortical vasculardementia. Expert Rev Neurother 5, 309-313.

[34] Chapuis C, Casez O, Lagrange E, Bedouch P, BessonG (2012) Hallucinations treated with rivastigmine inCreutzfeldt-Jakob disease. Fundam Clin Pharmacol 26,212-214.

[35] Stryjer R, Ophir D, Bar F, Spivak B, Weizman A, Strous RD(2012) Rivastigmine treatment for the prevention of elec-


troconvulsive therapy-induced memory deficits in patientswith schizophrenia. Clin Neuropharmacol 35, 161-164.

[36] Farlow MR, Grossberg GT, Sadowsky CH, Meng X, Somo-gyi M (2013) A 24-Week, Randomized, Controlled Trial ofRivastigmine Patch 13.3mg/24h Versus 4.6mg/24h in SevereAlzheimer’s Dementia. CNS Neurosci Ther 19, 745-752.

[37] Alva G, Isaacson R, Sadowsky C, Grossberg G, Meng X,Somogyi M (2014) Efficacy of higher-dose 13.3mg/24h(15cm) rivastigmine patch on the Alzheimer’s DiseaseAssessment Scale-cognitive subscale: Domain and indi-vidual item analysis. Int J Geriatr Psychiatry, doi:10.1002/gps.4080

[38] Raskind MA (2003) Update on Alzheimer drugs (galan-tamine). Neurologist 9, 235-240.

[39] Trinadhachari GN, Kamat AG, Prabahar KJ, Handa VK,Srinu KN, Babu KR, Sanasi PD (2013) Commercial scaleprocess of galanthamine hydrobromide involving Luchereduction: Galanthamine process involving regioselective1,2-reduction of alpha,beta-unsaturated ketone. Org ProcessRes Dev 17, 406-412.

[40] Trinadhachari GN, Kamat AG, Raghu BK, Sanasi PD,Prabahar KJ (2014) Stereoselective syntheses of galan-thamine and its stereoisomers by compementary Luche andL-selectride reductions. Tetrahedron Asymmetry 25, 117-124.

[41] Rao PP, Mohamed T, Osman W (2013) Investigating thebinding interactions of galantamine with beta-amyloid pep-tide. Bioorg Med Chem Lett 23, 239-243.

[42] Alexander KS, Wu HQ, Schwarcz R, Bruno JP (2012)Acute elevations of brain kynurenic acid impair cognitiveflexibility: Normalization by the alpha7 positive modulatorgalantamine. Psychopharmacology (Berl) 220, 627-637.

[43] Keller C, Kadir A, Forsberg A, Porras O, Nordberg A (2011)Long-term effects of galantamine treatment on brain func-tional activities as measured by PET in Alzheimer’s diseasepatients. J Alzheimers Dis 24, 109-123.

[44] Aarsland D, Hutchinson M, Larsen JP (2003) Cognitive,psychiatric and motor response to galantamine in Parkin-son’s disease with dementia. Int J Geriatr Psychiatry 18,937-941.

[45] Bora E, Veznedaroglu B, Kayahan B (2005) The effect ofgalantamine added to clozapine on cognition of five patientswith schizophrenia. Clin Neuropharmacol 28, 139-141.

[46] Craig D, Birks J (2006) Galantamine for vascular cognitiveimpairment. Cochrane Database Syst Rev, CD004746.

[47] Robinson DM, Plosker GL (2006) Galantamine extendedrelease. CNS Drugs 20, 673-681.

[48] Robinson DM, Plosker GL (2006) Galantamine extendedrelease in Alzheimer’s disease: Profile report. Drugs Aging23, 839-842.

[49] Maelicke A, Hoeffle-Maas A, Ludwig J, Maus A, Samo-chocki M, Jordis U, Koepke AK (2010) Memogain is agalantamine pro-drug having dramatically reduced adverseeffects and enhanced efficacy. J Mol Neurosci 40, 135-137.

[50] Hirasawa Y, Kobayashi J, Morita H (2009) The Lycopodiumalkaloids. Heterocycles 77, 679-729.

[51] Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, Gnanadeepam JM, Saiganesh R,Gibson F, He L, Behrens CH, Underiner G, Marturt J, FavreN (2012) Development of a large-scale synthetic route tomanufacture (-)-Huperzine A. Org Process Res Dev 16,635-642.

[52] Wang CY, Zheng W, Wang T, Xie JW, Wang SL, ZhaoBL, Teng WP, Wang ZY (2011) Huperzine A activatesWnt/beta-catenin signaling and enhances the nonamyloido-

genic pathway in an Alzheimer transgenic mouse model.Neuropsychopharmacology 36, 1073-1089.

[53] Ratia M, Gimenez-Llort L, Camps P, Munoz-Torrero D,Perez B, Clos MV, Badia A (2013) Huprine X and huperzineA improve cognition and regulate some neurochemical pro-cesses related with Alzheimer’s disease in triple transgenicmice (3xTg-AD). Neurodegener Dis 11, 129-140.

[54] Huang XT, Qian ZM, He X, Gong Q, Wu KC, Jiang LR,Lu LN, Zhu ZJ, Zhang HY, Yung WH, Ke Y (2014) Reduc-ing iron in the brain: A novel pharmacologic mechanismof huperzine A in the treatment of Alzheimer’s disease.Neurobiol Aging 35, 1045-1054.

[55] Rogers JT, Mikkilineni S, Cantuti-Castelvetri I, Smith DH,Huang X, Bandyopadhyay S, Cahill CM, MaccecchiniML, Lahiri DK, Greig NH (2011) The alpha-synuclein5’untranslated region targeted translation blockers: Anti-alpha synuclein efficacy of cardiac glycosides and Posiphen.J Neural Transm 118, 493-507.

[56] Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, BalliedierA, Greig NH, Rogers JT (2012) The anticholinesterasephenserine and its enantiomer posiphen as 5’untranslated-region-directed translation blockers of the Parkinson’s alphasynuclein expression. Parkinsons Dis 2012, 142372.

[57] Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H,Greig NH (2012) Posiphen as a candidate drug to lower CSFamyloid precursor protein, amyloid-beta peptide and tau lev-els: Target engagement, tolerability and pharmacokinetics inhumans. J Neurol Neurosurg Psychiatry 83, 894-902.

[58] Yu QS, Reale M, Kamal MA, Holloway HW, Luo W,Sambamurti K, Ray B, Lahiri DK, Rogers JT, GreigNH (2013) Synthesis of the Alzheimer drug Posipheninto its primary metabolic products (+)-N1-norPosiphen,(+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, theirinhibition of amyloid precursor protein, alpha-Synucleinsynthesis, interleukin-1beta release, and cholinergic action.Antiinflamm Antiallergy Agents Med Chem 12, 117-128.

[59] Lilja AM, Luo Y, Yu QS, Rojdner J, Li Y, Marini AM,Marutle A, Nordberg A, Greig NH (2013) Neurotrophic andneuroprotective actions of (-)- and (+)-phenserine, candidatedrugs for Alzheimer’s disease. PLoS One 8, e54887.

[60] Zhao X, Liang Y, Xu J, Zhang D, Wang D, Gu J, CuiY (2012) A single-center, randomized, open-label, dose-escalation study to evaluate the pharmacokinetics of tacrineanalogue octahydrogenacridine succinate tablets in healthyChinese subjects. Biol Pharm Bull 35, 1502-1508.

[61] Wang ZF, Yan J, Fu Y, Tang XC, Feng S, He XC, BaiDL (2008) Pharmacodynamic study of FS-0311: A novelhighly potent, selective acetylcholinesterase inhibitor. CellMol Neurobiol 28, 245-261.

[62] Lewis WG, Green LG, Grynszpan F, Radic Z, Carlier PR,Taylor P, Finn MG, Sharpless KB (2002) Click chemistry insitu: Acetylcholinesterase as a reaction vessel for the selec-tive assembly of a femtomolar inhibitor from an array ofbuilding blocks. Angew Chem Int Ed Engl 41, 1053-1057.

[63] Kortylewicz ZP, Baranowska-Kortylewicz J (2009) Radio-logic agents for monitoring Alzheimer’s disease progressionand evaluating a response to therapy and processes forthe preparation of such agents. US-20090117041, May-07-2009- Prior. Aug-10-2007.

[64] Gutierrez M, Matus MF, Poblete T, Amigo J, VallejosG, Astudillo L (2013) Isoxazoles: Synthesis, evaluationand bioinformatic design as acetylcholinesterase inhibitors.J Pharm Pharmacol 65, 1796-1804.

[65] Silva D, Chioua M, Samadi A, Agostinho P, GarcaoP, Lajarin-Cuesta R, de Los RC, Iriepa I, Moraleda I,


Gonzalez-Lafuente L, Mendes E, Perez C, Rodriguez-Franco MI, Marco-Contelles J, Carmo CM (2013)Synthesis, pharmacological assessment, and molecu-lar modeling of acetylcholinesterase/butyrylcholinesteraseinhibitors: Effect against amyloid-beta-induced neurotoxic-ity. ACS Chem Neurosci 4, 547-565.

[66] Sinha SK, Shrivastava SK (2013) Design, synthesis and eval-uation of some new 4-aminopyridine derivatives in learningand memory. Bioorg Med Chem Lett 23, 2984-2989.

[67] Sinha SK, Shrivastava SK (2013) Synthesis, evaluation andmolecular dynamics study of some new 4-aminopyridinesemicarbazones as an antiamnesic and cognition enhancingagents. Bioorg Med Chem 21, 5451-5460.

[68] Spilovska K, Korabecny J, Kral J, Horova A, Musilek K,Soukup O, Drtinova L, Gazova Z, Siposova K, Kuca K(2013) 7-Methoxytacrine-adamantylamine heterodimers ascholinesterase inhibitors in Alzheimer’s disease treatment–synthesis, biological evaluation and molecular modelingstudies. Molecules 18, 2397-2418.

[69] Di Pietro O, Viayna E, Vicente-Garcia E, Bartolini M,Ramon R, Juarez-Jimenez J, Clos MV, Perez B, AndrisanoV, Luque FJ, Lavilla R, Munoz-Torrero D (2014) 1,2,3,4-Tetrahydrobenzo[h][1, 6]naphthyridines as a new familyof potent peripheral-to-midgorge-site inhibitors of acetyl-cholinesterase: Synthesis, pharmacological evaluation andmechanistic studies. Eur J Med Chem 73, 141-152.

[70] Konrath EL, Passos CS, Klein-Junior LC, Henriques AT(2013) Alkaloids as a source of potential anticholinesteraseinhibitors for the treatment of Alzheimer’s disease. J PharmPharmacol 65, 1701-1725.

[71] Chen Y, Fang L, Peng S, Liao H, Lehmann J, Zhang Y(2012) Discovery of a novel acetylcholinesterase inhibitorby structure-based virtual screening techniques. Bioorg MedChem Lett 22, 3181-3187.

[72] Ambure P, Kar S, Roy K (2014) Pharmacophore mapping-based virtual screening followed by molecular dockingstudies in search of potential acetylcholinesterase inhibitorsas anti-Alzheimer’s agents. Biosystems 116, 10-20.

[73] Pang YP, Quiram P, Jelacic T, Hong F, BrimijoinS (1996) Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase.Steps toward novel drugs for treating Alzheimer’s disease.J Biol Chem 271, 23646-23649.

[74] Badia A, Banos JE, Camps P, Contreras J, Gorbig DM,Munoz-Torrero D, Simon M, Vivas NM (1998) Syn-thesis and evaluation of tacrine-huperzine A hybrids asacetylcholinesterase inhibitors of potential interest for thetreatment of Alzheimer’s disease. Bioorg Med Chem 6, 427-440.

[75] Camps P, El AR, Gorbig DM, Morral J, Munoz-Torrero D,Badia A, Eladi BJ, Vivas NM, Barril X, Orozco M, LuqueFJ (1999) Synthesis, in vitro pharmacology, and molecu-lar modeling of very potent tacrine-huperzine A hybrids asacetylcholinesterase inhibitors of potential interest for thetreatment of Alzheimer’s disease. J Med Chem 42, 3227-3242.

[76] Camps P, Cusack B, Mallender WD, El Achab RE, Mor-ral J, Munoz-Torrero D, Rosenberry TL (2000) HuprineX is a novel high-affinity inhibitor of acetylcholinesterasethat is of interest for treatment of Alzheimer’s disease. MolPharmacol 57, 409-417.

[77] Camps P, El AR, Morral J, Munoz-Torrero D, Badia A,Banos JE, Vivas NM, Barril X, Orozco M, Luque FJ (2000)New tacrine-huperzine A hybrids (huprines): Highly potenttight-binding acetylcholinesterase inhibitors of interest for

the treatment of Alzheimer’s disease. J Med Chem 43, 4657-4666.

[78] Camps P, Gomez E, Munoz-Torrero D, Badia A, Vivas NM,Barril X, Orozco M, Luque FJ (2001) Synthesis, in vitropharmacology, and molecular modeling of syn-huprines asacetylcholinesterase inhibitors. J Med Chem 44, 4733-4736.

[79] Camps P, Munoz-Torrero D (2001) Tacrine-huperzine Ahybrids (huprines): A new class of highly potent andselective acetylcholinesterase inhibitors of interest for thetreatment of Alzheimer’s disease. Mini Rev Med Chem 1,163-174.

[80] Carlier PR, Du DM, Han Y, Liu J, Pang YP (1999)Potent, easily synthesized huperzine A-tacrine hybridacetylcholinesterase inhibitors. Bioorg Med Chem Lett 9,2335-2338.

[81] Ronco C, Sorin G, Nachon F, Foucault R, Jean L, Romieu A,Renard PY (2009) Synthesis and structure-activity relation-ship of Huprine derivatives as human acetylcholinesteraseinhibitors. Bioorg Med Chem 17, 4523-4536.

[82] Ronco C, Foucault R, Gillon E, Bohn P, Nachon F, Jean L,Renard PY (2011) New huprine derivatives functionalizedat position 9 as highly potent acetylcholinesterase inhibitors.ChemMedChem 6, 876-888.

[83] Ronco C, Carletti E, Colletier JP, Weik M, Nachon F, JeanL, Renard PY (2012) Huprine derivatives as sub-nanomolarhuman acetylcholinesterase inhibitors: From rational designto validation by X-ray crystallography. ChemMedChem 7,400-405.

[84] Alcala MM, Vivas NM, Hospital S, Camps P, Munoz-Torrero D, Badia A (2003) Characterisation of theanticholinesterase activity of two new tacrine-huperzine Ahybrids. Neuropharmacology 44, 749-755.

[85] Dvir H, Wong DM, Harel M, Barril X, Orozco M, LuqueFJ, Munoz-Torrero D, Camps P, Rosenberry TL, SilmanI, Sussman JL (2002) 3D structure of Torpedo californicaacetylcholinesterase complexed with huprine X at 2.1 Aresolution: Kinetic and molecular dynamic correlates. Bio-chemistry 41, 2970-2981.

[86] Ratia M, Gimenez-Llort L, Camps P, Munoz-Torrero D, ClosMV, Badia A (2010) Behavioural effects and regulation ofPKCalpha and MAPK by huprine X in middle aged mice.Pharmacol Biochem Behav 95, 485-493.

[87] Nachon F, Carletti E, Ronco C, Trovaslet M, Nicolet Y,Jean L, Renard PY (2013) Crystal structures of humancholinesterases in complex with huprine W and tacrine:Elements of specificity for anti-Alzheimer’s drugs targetingacetyl- and butyryl-cholinesterase. Biochem J 453, 393-399.

[88] Gemma S, Gabellieri E, Huleatt P, Fattorusso C, BorrielloM, Catalanotti B, Butini S, De AM, Novellino E, Nacci V,Belinskaya T, Saxena A, Campiani G (2006) Discovery ofhuperzine A-tacrine hybrids as potent inhibitors of humancholinesterases targeting their midgorge recognition sites.J Med Chem 49, 3421-3425.

[89] Pavlic M (1970) The inhibition of butyrylcholinesterase bymethanesulfonyl fluoride. Biochim Biophys Acta 198, 389-391.

[90] Krupka RM (1974) Methanesulfonyl fluoride inactivationof acetylcholinesterase in the presence of substrates andreversible inhibitors. Biochim Biophys Acta 370, 197-207.

[91] Malin DH, Toups PJ, Osgood LD, Fowler DE, Hunter CL,Arcangeli KR, Moss DE (1991) Methanesulfonyl fluorideenhances one-trial reward learning in mid-aged rats. Neuro-biol Aging 12, 181-183.

[92] Malin DH, Plotner RE, Radulescu SJ, Ferebee RN, Lake JR,Negrete PG, Schaefer PJ, Crothers MK, Moss DE (1993)


Chronic methanesulfonyl fluoride enhances one-trial perday reward learning in aged rats. Neurobiol Aging 14, 393-395.

[93] Palacios-Esquivel RL, Pacheco G, Moss DE (1993)Methanesulfonyl fluoride (MSF) blocks scopolamine-induced amnesia in rats. Neurobiol Aging 14, 93-96.

[94] Borlongan CV, Sumaya IC, Moss DE (2005) Methanesul-fonyl fluoride, an acetylcholinesterase inhibitor, attenuatessimple learning and memory deficits in ischemic rats. BrainRes 1038, 50-58.

[95] Moss DE, Berlanga P, Hagan MM, Sandoval H, Ishida C(1999) Methanesulfonyl fluoride (MSF): A double-blind,placebo-controlled study of safety and efficacy in the treat-ment of senile dementia of the Alzheimer type. AlzheimerDis Assoc Disord 13, 20-25.

[96] Thatte U (2005) Phenserine Axonyx. Curr Opin InvestigDrugs 6, 729-739.

[97] Klein J (2007) Phenserine. Expert Opin Investig Drugs 16,1087-1097.

[98] Kadir A, Andreasen N, Almkvist O, Wall A, Forsberg A,Engler H, Hagman G, Larksater M, Winblad B, ZetterbergH, Blennow K, Langstrom B, Nordberg A (2008) Effect ofphenserine treatment on brain functional activity and amy-loid in Alzheimer’s disease. Ann Neurol 63, 621-631.

[99] Winblad B, Giacobini E, Frolich L, Friedhoff LT, BruinsmaG, Becker RE, Greig NH (2010) Phenserine efficacy inAlzheimer’s disease. J Alzheimers Dis 22, 1201-1208.

[100] Becker RE, Greig NH (2013) Fire in the ashes: Can failedAlzheimer’s disease drugs succeed with second chances?Alzheimers Dement 9, 50-57.

[101] Cerasoli DM, Griffiths EM, Doctor BP, Saxena A, FedorkoJM, Greig NH, Yu QS, Huang Y, Wilgus H, Karatzas CN,Koplovitz I, Lenz DE (2005) In vitro and in vivo char-acterization of recombinant human butyrylcholinesterase(Protexia) as a potential nerve agent bioscavenger. ChemBiol Interact 157-158, 363-365.

[102] Mumford H, Troyer JK (2011) Post-exposure therapy withrecombinant human BuChE following percutaneous VXchallenge in guinea-pigs. Toxicol Lett 206, 29-34.

[103] Park SJ, Jung HJ, Son MS, Jung JM, Kim DH, Jung IH,Cho YB, Lee EH, Ryu JH (2012) Neuroprotective effectsof INM-176 against lipopolysaccharide-induced neuronalinjury. Pharmacol Biochem Behav 101, 427-433.

[104] Park SJ, Jung JM, Lee HE, Lee YW, Kim DH, Kim JM,Hong JG, Lee CH, Jung IH, Cho YB, Jang DS, Ryu JH(2012) The memory ameliorating effects of INM-176, anethanolic extract of Angelica gigas, against scopolamine-or Abeta(1-42)-induced cognitive dysfunction in mice.J Ethnopharmacol 143, 611-620.

[105] Bolea I, Gella A, Unzeta M (2013) Propargylamine-derivedmultitarget-directed ligands: Fighting Alzheimer’s diseasewith monoamine oxidase inhibitors. J Neural Transm 120,893-902.

[106] Leon R, Garcia AG, Marco-Contelles J (2013) Recentadvances in the multitarget-directed ligands approach forthe treatment of Alzheimer’s disease. Med Res Rev 33,139-189.

[107] Starks KM, Ortega-Vilain AC, Buccafusco JJ, Powers JC(1996) Novel pyridinium derivatives as inhibitors for acetyl-cholinesterase. J Enzyme Inhib 10, 27-45.

[108] Buccafusco JJ, Powers JC, Hernandez MA, PrendergastMA, Terry AV, Jonnala RR (2007) MHP-133, a drug withmultiple CNS targets: Potential for neuroprotection andenhanced cognition. Neurochem Res 32, 1224-1237.

[109] Borroni E, Damsma G, Giovacchini C, Mutel V, Jakob-Rotne R, Da PM (1994) A novel acetylcholinesteraseinhibitor, Ro 46-5934, which interacts with muscarinic M2receptors. Biochem Soc Trans 22, 755-758.

[110] Hou LN, Xu JR, Zhao QN, Gao XL, Cui YY, Xu J, WangH, Chen HZ (2014) A new motif in the N-terminal ofacetylcholinesterase triggers amyloid-beta aggregation anddeposition. CNS Neurosci Ther 20, 59-66.

[111] Shao BY, Xia Z, Xie Q, Ge XX, Zhang WW, Sun J, JiangP, Wang H, Le WD, Qiu ZB, Lu Y, Chen HZ (2014)Meserine, a novel carbamate AChE inhibitor, amelioratesscopolamine-induced dementia and alleviates amyloidoge-nesis of APP/PS1 transgenic mice. CNS Neurosci Ther 20,165-171.

[112] Mao F, Huang L, Luo Z, Liu A, Lu C, Xie Z, Li X (2012)O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: Mul-tifunctional biometals chelators, antioxidants, and inhibitorsof cholinesterase activity and amyloid-beta aggregation.Bioorg Med Chem 20, 5884-5892.

[113] Wang Y, Wang F, Yu JP, Jiang FC, Guan XL, WangCM, Li L, Cao H, Li MX, Chen JG (2012) Novel mul-tipotent phenylthiazole-tacrine hybrids for the inhibitionof cholinesterase activity, beta-amyloid aggregation andCa(2+) overload. Bioorg Med Chem 20, 6513-6522.

[114] Catto M, Berezin AA, Lo RD, Loizou G, DemetriadesM, De SA, Campagna F, Koutentis PA, Carotti A (2012)Design, synthesis and biological evaluation of benzo[e][1, 2,4]triazin-7(1H)-one and [1, 2, 4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloidaggregation and acetyl/butyryl cholinesterase. Eur J MedChem 58, 84-97.

[115] Ozturan Oezer E, Unsal TO, Ozadali K, Kucukkil-inc T, Balkan A, Ucar G (2013) Synthesis, molecularmodeling and evaluation of novel N’-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitorsfor cholinesterases and Abeta aggregation. Bioorg MedChem Lett 23, 440-443.

[116] Telpoukhovskaia MA, Patrick BO, Rodriguez-RodriguezC, Orvig C (2013) Exploring the multifunctionality ofthioflavin- and deferiprone-based molecules as acetyl-cholinesterase inhibitors for potential application inAlzheimer’s disease. Mol Biosyst 9, 792-805.

[117] Veloso AJ, Dhar D, Chow AM, Zhang B, Tang DW,Ganesh HV, Mikhaylichenko S, Brown IR, Kerman K(2013) sym-Triazines for directed multitarget modulationof cholinesterases and amyloid-beta in Alzheimer’s disease.ACS Chem Neurosci 4, 339-349.

[118] Veloso AJ, Chow AM, Dhar D, Tang DW, Ganesh HV,Mikhaylichenko S, Brown IR, Kerman K (2013) Biologicalactivity of sym-triazines with acetylcholine-like substitu-tions as multitarget modulators of Alzheimer’s disease. ACSChem Neurosci 4, 924-929.

[119] Prinz M, Parlar S, Bayraktar G, Alptuzun V, Erciyas E, Fal-larero A, Karlsson D, Vuorela P, Burek M, Forster C, TuruncE, Armagan G, Yalcin A, Schiller C, Leuner K, Krug M,Sotriffer CA, Holzgrabe U (2013) 1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, andamyloid-beta aggregation crossing the blood-brain barrier.Eur J Pharm Sci 49, 603-613.

[120] Keri RS, Quintanova C, Marques SM, Esteves AR, CardosoSM, Santos MA (2013) Design, synthesis and neuropro-tective evaluation of novel tacrine-benzothiazole hybridsas multi-targeted compounds against Alzheimer’s disease.Bioorg Med Chem 21, 4559-4569.


[121] Badran MM, Abdel Hakeem M, Abuel-Maaty SM, El-Malah A, Abdel Salam RM (2010) Design, synthesis,and molecular-modeling study of aminothienopyridine ana-logues of tacrine for Alzheimer’s disease. Arch Pharm(Weinheim) 343, 590-601.

[122] El-Malah A, Gedawy EM, Kassab AE, Salam RM (2014)Novel tacrine analogs as potential cholinesterase inhibitorsin Alzheimer’s disease. Arch Pharm (Weinheim) 347, 96-103.

[123] Viayna E, Sola I, Bartolini M, De SA, Tapia-RojasC, Serrano FG, Sabate R, Juarez-Jimenez J, Perez B,Luque FJ, Andrisano V, Clos MV, Inestrosa NC, Munoz-Torrero D (2014) Synthesis and multitarget biologicalprofiling of a novel family of rhein derivatives asdisease-modifying anti-Alzheimer agents. J Med Chem 57,2549-2567.

[124] Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W,Tan Z, Deng Y (2014) Design, synthesis and evaluation ofgenistein-O-alkylbenzylamines as potential multifunctionalagents for the treatment of Alzheimer’s disease. Eur J MedChem 76C, 314-331.

[125] Fang L, Fang X, Gou S, Lupp A, Lenhardt I, Sun Y, HuangZ, Chen Y, Zhang Y, Fleck C (2014) Design, synthesis andbiological evaluation of D-ring opened galantamine analogsas multifunctional anti-Alzheimer agents. Eur J Med Chem76C, 376-386.

[126] Vyas NA, Bhat SS, Kumbhar AS, Sonawane UB, JaniV, Joshi RR, Ramteke SN, Kulkarni PP, Joshi B (2014)Ruthenium(II) polypyridyl complex as inhibitor of acetyl-cholinesterase and Abeta aggregation. Eur J Med Chem 75,375-381.

[127] del Monte-Millan M, Garcia-Palomero E, Valenzuela R,Usan P, de AC, Munoz-Ruiz P, Rubio L, Dorronsoro I,Martinez A, Medina M (2006) Dual binding site acetyl-cholinesterase inhibitors: Potential new disease-modifyingagents for AD. J Mol Neurosci 30, 85-88.

[128] Garcia-Palomero E, Munoz P, Usan P, Garcia P, DelgadoE, De AC, Valenzuela R, Rubio L, Medina M, Martinez A(2008) Potent beta-amyloid modulators. Neurodegener Dis5, 153-156.

[129] Luo W, Su YB, Hong C, Tian RG, Su LP, Wang YQ, Li Y,Yue JJ, Wang CJ (2013) Design, synthesis and evaluationof novel 4-dimethylamine flavonoid derivatives as potentialmulti-functional anti-Alzheimer agents. Bioorg Med Chem21, 7275-7282.

[130] Friggeri L, De Vita D., Pandolfi F, Tortorella S, CostiR, Di Santo R., Scipione L (2014) Design, synthesisand evaluation of 3,4-dihydroxybenzoic acid derivativesas antioxidants, bio-metal chelating agents and acetyl-cholinesterase inhibitors. J Enzyme Inhib Med Chem, doi:10.3109/14756366.2013.866657

[131] Luo Z, Sheng J, Sun Y, Lu C, Yan J, Liu A, Luo HB, HuangL, Li X (2013) Synthesis and evaluation of multi-target-directed ligands against Alzheimer’s disease based on thefusion of donepezil and ebselen. J Med Chem 56, 9089-9099.

[132] Luo Z, Liang L, Sheng J, Pang Y, Li J, Huang L, Li X(2014) Synthesis and biological evaluation of a new series ofebselen derivatives as glutathione peroxidase (GPx) mimicsand cholinesterase inhibitors against Alzheimer’s disease.Bioorg Med Chem 22, 1355-1361.

[133] Oset-Gasque MJ, Gonzalez MP, Perez-Pena J, Garcia-FontN, Romero A, Pino JD, Ramos E, Hadjipavlou-LitinaD, Soriano E, Chioua M, Samadi A, Raghuvanshi DS,Singh KN, Marco-Contelles J (2014) Toxicological andpharmacological evaluation, antioxidant, ADMET and

molecular modeling of selected racemic chromenotacrines{11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols} for the potential prevention andtreatment of Alzheimer’s disease. Eur J Med Chem 74,491-501.

[134] Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O,Reubroycharoen P, Tohda M, Boonyarat C (2014) Synthe-sis, biological evaluation and molecular modeling study ofnovel tacrine-carbazole hybrids as potential multifunctionalagents for the treatment of Alzheimer’s disease. Eur J MedChem 75, 21-30.

[135] Pudlo M, Luzet V, Ismaili L, Tomassoli I, Iutzeler A,Refouvelet B (2014) Quinolone-benzylpiperidine deriva-tives as novel acetylcholinesterase inhibitor and antioxidanthybrids for Alzheimer Disease. Bioorg Med Chem 22, 2496-2507.

[136] Lopez-Iglesias B, Perez C, Morales-Garcia JA, Alonso-GilS, Perez-Castillo A, Romero A, Lopez MG, Villarroya M,Conde S, Rodriguez-Franco MI (2014) New melatonin-N,N-dibenzyl(N-methyl)amine hybrids: Potent neurogenicagents with antioxidant, cholinergic, and neuroprotectiveproperties as innovative drugs for Alzheimer’s disease.J Med Chem 57, 3773-3785.

[137] Chen Y, Sun J, Huang Z, Liao H, Peng S, Lehmann J,Zhang Y (2013) Design, synthesis and evaluation of tacrine-flurbiprofen-nitrate trihybrids as novel anti-Alzheimer’sdisease agents. Bioorg Med Chem 21, 2462-2470.

[138] Chen Y, Sun J, Peng S, Liao H, Zhang Y, Lehmann J (2013)Tacrine-flurbiprofen hybrids as multifunctional drug candi-dates for the treatment of Alzheimer’s disease. Arch Pharm(Weinheim) 346, 865-871.

[139] Chen Y, Sun J, Huang Z, Liao H, Peng S, Lehmann J,Zhang Y (2013) NO-donating tacrine derivatives as potentialbutyrylcholinesterase inhibitors with vasorelaxation activ-ity. Bioorg Med Chem Lett 23, 3162-3165.

[140] Gonzalez-Naranjo P, Perez-Macias N, Campillo NE, PerezC, Aran VJ, Giron R, Sanchez-Robles E, Martin MI, Gomez-Canas M, Garcia-Arencibia M, Fernandez-Ruiz J, Paez JA(2014) Cannabinoid agonists showing BuChE inhibition aspotential therapeutic agents for Alzheimer’s disease. Eur JMed Chem 73, 56-72.

[141] Lange JH, Coolen HK, van der Neut MA, Borst AJ, StorkB, Verveer PC, Kruse CG (2010) Design, synthesis, bio-logical properties, and molecular modeling investigationsof novel tacrine derivatives with a combination of acetyl-cholinesterase inhibition and cannabinoid CB1 receptorantagonism. J Med Chem 53, 1338-1346.

[142] Chen PY, Tsai CT, Ou CY, Hsu WT, Jhuo MD, WuCH, Shih TC, Cheng TH, Chung JG (2012) Compu-tational analysis of novel drugs designed for use asacetylcholinesterase inhibitors and histamine H3 receptorantagonists for Alzheimer’s disease by docking, scoring andde novo evolution. Mol Med Rep 5, 1043-1048.

[143] Bolea I, Juarez-Jimenez J, de Los Rios C, Chioua M, Pou-plana R, Luque FJ, Unzeta M, Marco-Contelles J, SamadiA (2011) Synthesis, biological evaluation, and molecularmodeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-aminehybrids as new multipotent cholinesterase/monoamineoxidase inhibitors for the treatment of Alzheimer’s disease.J Med Chem 54, 8251-8270.

[144] Bolea I, Gella A, Monjas L, Perez C, Rodriguez-FrancoMI, Marco-Contelles J, Samadi A, Unzeta M (2013)Multipotent, permeable drug ASS234 inhibits Abeta aggre-gation, possesses antioxidant properties and protects from


Abeta-induced apoptosis in vitro. Curr Alzheimer Res 10,797-808.

[145] Bautista-Aguilera OM, Esteban G, Bolea I, Nikolic K,Agbaba D, Moraleda I, Iriepa I, Samadi A, Soriano E, UnzetaM, Marco-Contelles J (2014) Design, synthesis, pharmaco-logical evaluation, QSAR analysis, molecular modeling andADMET of novel donepezil-indolyl hybrids as multipotentcholinesterase/monoamine oxidase inhibitors for the poten-tial treatment of Alzheimer’s disease. Eur J Med Chem 75C,82-95.

[146] Zheng H, Fridkin M, Youdim MB (2012) Novel chela-tors targeting cell cycle arrest, acetylcholinesterase, andmonoamine oxidase for Alzheimer’s therapy. Curr DrugTargets 13, 1089-1106.

[147] Zheng W, Li J, Qiu Z, Xia Z, Li W, Yu L, Chen H, Chen J,Chen Y, Hu Z, Zhou W, Shao B, Cui Y, Xie Q, Chen H (2012)Novel bis-(-)-nor-meptazinol derivatives act as dual bind-ing site AChE inhibitors with metal-complexing property.Toxicol Appl Pharmacol 264, 65-72.

[148] Liu T, Xia Z, Zhang WW, Xu JR, Ge XX, Li J, Cui Y,Qiu ZB, Xu J, Xie Q, Wang H, Chen HZ (2013) Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potentlyameliorates scopolamine-induced cognitive deficits in mice.Pharmacol Biochem Behav 104, 138-143.

[149] Geldenhuys WJ, Van der Schyf CJ (2013) Rationallydesigned multi-targeted agents against neurodegenerativediseases. Curr Med Chem 20, 1662-1672.

[150] Ding Y, Ko MH, Pehar M, Kotch F, Peters NR, Luo Y,Salamat SM, Puglielli L (2012) Biochemical inhibition ofthe acetyltransferases ATase1 and ATase2 reduces beta-secretase (BACE1) levels and Abeta generation. J Biol Chem287, 8424-8433.

[151] Tan Z, Turner RC, Leon RL, Li X, Hongpaisan J, ZhengW, Logsdon AF, Naser ZJ, Alkon DL, Rosen CL, Huber JD(2013) Bryostatin improves survival and reduces ischemicbrain injury in aged rats after acute ischemic stroke. Stroke44, 3490-3497.

[152] Boddapati S, Levites Y, Sierks MR (2011) Inhibiting beta-secretase activity in Alzheimer’s disease cell models withsingle-chain antibodies specifically targeting APP. J MolBiol 405, 436-447.

[153] Boddapati S, Levites Y, Suryadi V, Kasturirangan S,Sierks MR (2012) Bispecific tandem single chain anti-body simultaneously inhibits beta-secretase and promotesalpha-secretase processing of AbetaPP. J Alzheimers Dis 28,961-969.

[154] Vassar R, Kovacs DM, Yan R, Wong PC (2009) The beta-secretase enzyme BACE in health and Alzheimer’s disease:Regulation, cell biology, function, and therapeutic potential.J Neurosci 29, 12787-12794.

[155] Vassar R, Kandalepas PC (2011) The beta-secretase enzymeBACE1 as a therapeutic target for Alzheimer’s disease.Alzheimers Res Ther 3, 20.

[156] Holsinger RM, Goense N, Bohorquez J, Strappe P (2013)Splice variants of the Alzheimer’s disease beta-secretase,BACE1. Neurogenetics 14, 1-9.

[157] Tamagno E, Guglielmotto M, Monteleone D, Vercelli A,Tabaton M (2012) Transcriptional and post-transcriptionalregulation of beta-secretase. IUBMB Life 64, 943-950.

[158] Shahani N, Pryor W, Swarnkar S, Kholodilov N, ThinakaranG, Burke RE, Subramaniam S (2014) Rheb GTPase reg-ulates beta-secretase levels and amyloid beta generation.J Biol Chem 289, 5799-5808.

[159] Ghosh AK, Venkateswara RK, Yadav ND, Anderson DD,Gavande N, Huang X, Terzyan S, Tang J (2012) Structure-

based design of highly selective beta-secretase inhibitors:Synthesis, biological evaluation, and protein-ligand X-raycrystal structure. J Med Chem 55, 9195-9207.

[160] Hamada Y, Kiso Y (2013) Advances in the identificationof beta-secretase inhibitors. Expert Opin Drug Discov 8,709-731.

[161] Evin G, Hince C (2013) BACE1 as a therapeutic target inAlzheimer’s disease: Rationale and current status. DrugsAging 30, 755-764.

[162] Mikulca JA, Nguyen V, Gajdosik DA, Teklu SG, Giunta EA,Lessa EA, Tran CH, Terak EC, Raffa RB (2014) Potentialnovel targets for Alzheimer pharmacotherapy: II. Update onsecretase inhibitors and related approaches. J Clin PharmTher 39, 25-37.

[163] Yan R, Vassar R (2014) Targeting the beta secretase BACE1for Alzheimer’s disease therapy. Lancet Neurol 13, 319-329.

[164] Ghosh AK, Osswald HL (2014) BACE1 (beta-secretase)inhibitors for the treatment of Alzheimer’s disease. ChemSoc Rev, doi: 10.1039/C3CS60460H

[165] Burt J (2010) American Chemical Society – 240th nationalmeeting – chemistry for preventing and combating disease:Part 1. IDrugs 13, 669-672.

[166] Mandal M, Zhu Z, Cumming JN, Liu X, Strickland C, Maz-zola RD, Caldwell JP, Leach P, Grzelak M, Hyde L, ZhangQ, Terracina G, Zhang L, Chen X, Kuvelkar R, KennedyME, Favreau L, Cox K, Orth P, Buevich A, Voigt J, WangH, Kazakevich I, McKittrick BA, Greenlee W, Parker EM,Stamford AW (2012) Design and validation of bicycliciminopyrimidinones as beta amyloid cleaving enzyme-1(BACE1) inhibitors: Conformational constraint to favor abioactive conformation. J Med Chem 55, 9331-9345.

[167] Congreve M, Aharony D, Albert J, Callaghan O, Campbell J,Carr RA, Chessari G, Cowan S, Edwards PD, FredericksonM, McMenamin R, Murray CW, Patel S, Wallis N (2007)Application of fragment screening by X-ray crystallographyto the discovery of aminopyridines as inhibitors of beta-secretase. J Med Chem 50, 1124-1132.

[168] Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik D,Callaghan O, Campbell JB, Carr RA, Chessari G, CongreveM, Frederickson M, Folmer RH, Geschwindner S, KoetherG, Kolmodin K, Krumrine J, Mauger RC, Murray CW, Ols-son LL, Patel S, Spear N, Tian G (2007) Application offragment-based lead generation to the discovery of novel,cyclic amidine beta-secretase inhibitors with nanomolarpotency, cellular activity, and high ligand efficiency. J MedChem 50, 5912-5925.

[169] Geschwindner S, Olsson LL, Albert JS, Deinum J, EdwardsPD, de BT, Folmer RH (2007) Discovery of a novel warheadagainst beta-secretase through fragment-based lead genera-tion. J Med Chem 50, 5903-5911.

[170] Murray CW, Callaghan O, Chessari G, Cleasby A, CongreveM, Frederickson M, Hartshorn MJ, McMenamin R, PatelS, Wallis N (2007) Application of fragment screening byX-ray crystallography to beta-secretase. J Med Chem 50,1116-1123.

[171] Gravenfors Y, Viklund J, Blid J, Ginman T, Karlstrom S,Kihlstrom J, Kolmodin K, Lindstrom J, von BS, von KF,Bogar K, Slivo C, Swahn BM, Olsson LL, Johansson P, Eket-jall S, Falting J, Jeppsson F, Stromberg K, Janson J, RahmF (2012) New aminoimidazoles as beta-secretase (BACE-1)inhibitors showing amyloid-beta (Abeta) lowering in brain.J Med Chem 55, 9297-9311.

[172] Ginman T, Viklund J, Malmstrom J, Blid J, Emond R, Fors-blom R, Johansson A, Kers A, Lake F, Sehgelmeble F, SterkyKJ, Bergh M, Lindgren A, Johansson P, Jeppsson F, Falting


J, Gravenfors Y, Rahm F (2013) Core refinement toward per-meable beta-secretase (BACE-1) inhibitors with low hERGactivity. J Med Chem 56, 4181-4205.

[173] Yonezawa S, Yamamoto T, Yamakawa H, Muto C, HosonoM, Hattori K, Higashino K, Yutsudo T, Iwamoto H, KondoY, Sakagami M, Togame H, Tanaka Y, Nakano T, TakemotoH, Arisawa M, Shuto S (2012) Conformational restrictionapproach to beta-secretase (BACE1) inhibitors: Effect of acyclopropane ring to induce an alternative binding mode. JMed Chem 55, 8838-8858.

[174] Yonezawa S, Yamakawa H, Muto C, Hosono M, YamamotoT, Hattori K, Sakagami M, Togame H, Tanaka Y, Nakano T,Takemoto H, Arisawa M, Shuto S (2013) Conformationalrestriction approach to BACE1 inhibitors II: SAR study ofthe isocytosine derivatives fixed with a cis-cyclopropanering. Bioorg Med Chem Lett 23, 2912-2915.

[175] Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T,Hirode M, Sagayama M, Maeda R, Kawamoto M, HiraiK, Terauchi J, Sakura Y, Kakihana M, Kato K, Iwat-subo T, Miyamoto M (2010) A noncompetitive BACE1inhibitor TAK-070 ameliorates Abeta pathology and behav-ioral deficits in a mouse model of Alzheimer’s disease.J Neurosci 30, 11157-11166.

[176] Takahashi H, Fukumoto H, Maeda R, Terauchi J, KatoK, Miyamoto M (2010) Ameliorative effects of a non-competitive BACE1 inhibitor TAK-070 on Abeta peptidelevels and impaired learning behavior in aged rats. BrainRes 1361, 146-156.

[177] Cheng Y, Judd TC, Bartberger MD, Brown J, Chen K, Fre-meau RT Jr, Hickman D, Hitchcock SA, Jordan B, Li V,Lopez P, Louie SW, Luo Y, Michelsen K, Nixey T, Pow-ers TS, Rattan C, Sickmier EA, St JD Jr, Wahl RC, WenPH, Wood S (2011) From fragment screening to in vivoefficacy: Optimization of a series of 2-aminoquinolinesas potent inhibitors of beta-site amyloid precursor pro-tein cleaving enzyme 1 (BACE1). J Med Chem 54,5836-5857.

[178] Dineen TA, Weiss MM, Williamson T, Acton P, Babu-KhanS, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M,Croghan MD, Dunn RT, Esmay J, Graceffa RF, Harried SS,Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V,Lopez P, Louie S, Monenschein H, Nguyen TT, PenningtonLD, San MT, Sickmier EA, Vargas HM, Wahl RC, Wen PH,Whittington DA, Wood S, Xue Q, Yang BH, Patel VF, ZhongW (2012) Design and synthesis of potent, orally efficacioushydroxyethylamine derived beta-site amyloid precursor pro-tein cleaving enzyme (BACE1) inhibitors. J Med Chem 55,9025-9044.

[179] Weiss MM, Williamson T, Babu-Khan S, Bartberger MD,Brown J, Chen K, Cheng Y, Citron M, Croghan MD,Dineen TA, Esmay J, Graceffa RF, Harried SS, HickmanD, Hitchcock SA, Horne DB, Huang H, Imbeah-AmpiahR, Judd T, Kaller MR, Kreiman CR, La DS, Li V, LopezP, Louie S, Monenschein H, Nguyen TT, Pennington LD,Rattan C, San MT, Sickmier EA, Wahl RC, Wen PH,Wood S, Xue Q, Yang BH, Patel VF, Zhong W (2012)Design and preparation of a potent series of hydroxyethy-lamine containing beta-secretase inhibitors that demonstraterobust reduction of central beta-amyloid. J Med Chem 55,9009-9024.

[180] Huang H, La DS, Cheng AC, Whittington DA, Patel VF,Chen K, Dineen TA, Epstein O, Graceffa R, Hickman D,Kiang YH, Louie S, Luo Y, Wahl RC, Wen PH, Wood S,Fremeau RT Jr (2012) Structure- and property-based design

of aminooxazoline xanthenes as selective, orally efficacious,and CNS penetrable BACE inhibitors for the treatment ofAlzheimer’s disease. J Med Chem 55, 9156-9169.

[181] Wood S, Wen PH, Zhang J, Zhu L, Luo Y, Babu-Khan S, Chen K, Pham R, Esmay J, Dineen TA, KallerMR, Weiss MM, Hitchcock SA, Citron M, Zhong W,Hickman D, Williamson T (2012) Establishing the rela-tionship between in vitro potency, pharmacokinetic, andpharmacodynamic parameters in a series of orally avail-able, hydroxyethylamine-derived beta-secretase inhibitors.J Pharmacol Exp Ther 343, 460-467.

[182] Pennington LD, Whittington DA, Bartberger MD, JordanSR, Monenschein H, Nguyen TT, Yang BH, Xue QM,Vounatsos F, Wahl RC, Chen K, Wood S, Citron M, PatelVF, Hitchcock SA, Zhong W (2013) Hydroxyethylamine-based inhibitors of BACE1: P(1)-P(3) macrocyclization canimprove potency, selectivity, and cell activity. Bioorg MedChem Lett 23, 4459-4464.

[183] Hunt KW, Cook AW, Watts RJ, Clark CT, Vigers G, SmithD, Metcalf AT, Gunawardana IW, Burkard M, Cox AA,Geck Do MK, Dutcher D, Thomas AA, Rana S, Kallan NC,Delisle RK, Rizzi JP, Regal K, Sammond D, Groneberg R,Siu M, Purkey H, Lyssikatos JP, Marlow A, Liu X, TangTP (2013) Spirocyclic beta-site amyloid precursor proteincleaving enzyme 1 (BACE1) inhibitors: From hit to lower-ing of cerebrospinal fluid (CSF) amyloid beta in a higherspecies. J Med Chem 56, 3379-3403.

[184] Thomas AA, Hunt KW, Volgraf M, Watts RJ, Liu X, VigersG, Smith D, Sammond D, Tang TP, Rhodes SP, Metcalf AT,Brown KD, Otten JN, Burkard M, Cox AA, Do MK, DutcherD, Rana S, Delisle RK, Regal K, Wright AD, GronebergR, Scearce-Levie K, Siu M, Purkey HE, Lyssikatos JP,Gunawardana IW (2014) Discovery of 7-Tetrahydropyran-2-yl chromans: Beta-site amyloid precursor protein cleavingEnzyme 1 (BACE1) inhibitors that reduce amyloid beta-protein (Abeta) in the central nervous system. J Med Chem57, 878-902.

[185] Eketjall S, Janson J, Jeppsson F, Svanhagen A, KolmodinK, Gustavsson S, Radesater AC, Eliason K, Briem S,Appelkvist P, Niva C, Berg AL, Karlstrom S, Swahn BM,Falting J (2013) AZ-4217: A high potency BACE inhibitordisplaying acute central efficacy in different in vivo modelsand reduced amyloid deposition in Tg2576 mice. J Neurosci33, 10075-10084.

[186] Cheng X, Zhou Y, Gu W, Wu J, Nie A, Cheng J, Zhou J,Zhou W, Zhang Y (2013) The selective BACE1 inhibitor viareduces amyloid-beta production in cell and mouse modelsof Alzheimer’s disease. J Alzheimers Dis 37, 823-834.

[187] Liu X, Wong H, Scearce-Levie K, Watts RJ, CoraggioM, Shin YG, Peng K, Wildsmith KR, Atwal JK, MangoJ, Schauer SP, Regal K, Hunt KW, Thomas AA, Siu M,Lyssikatos J, Deshmukh G, Hop CE (2013) Mechanisticpharmacokinetic-pharmacodynamic modeling of BACE1inhibition in monkeys: Development of a predictive modelfor amyloid precursor protein processing. Drug Metab Dis-pos 41, 1319-1328.

[188] Takahashi R, Ma S, Deese A, Yue Q, Kim-Kang H, YiY, Siu M, Hunt KW, Kallan NC, Hop CE, Liu X, Kho-jasteh SC (2014) Elucidating the mechanism of cytochromeP450-mediated pyrimidine ring conversion to pyrazolemetabolites with the BACE1 inhibitor GNE-892 in rats.Drug Metab Dispos 42, 890-898.

[189] Takahashi R, Ma S, Yue Q, Kim-Kang H, Yi Y, Lyssikatos JP,Regal K, Hunt KW, Kallan NC, Siu M, Hop CE, Liu X, Kho-jasteh SC (2014) Dose-dependent exposure and metabolism


of GNE-892, a beta-secretase inhibitor, in monkeys: Con-tributions by P450, AO, and P-gp. Eur J Drug MetabPharmacokinet, doi: 10.1007/s13318-014-0198-5

[190] Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G,Holtzman DM, Ghosh AK, Tang J (2011) Beta-secretaseinhibitor GRL-8234 rescues age-related cognitive declinein APP transgenic mice. FASEB J 25, 775-784.

[191] Zhu Z, Li C, Wang X, Yang Z, Chen J, Hu L, Jiang H,Shen X (2010) 2,2’,4’-trihydroxychalcone from Glycyrrhizaglabra as a new specific BACE1 inhibitor efficiently amelio-rates memory impairment in mice. J Neurochem 114, 374-385.

[192] Tounge BA, Reynolds CH (2003) Calculation of the bindingaffinity of beta-secretase inhibitors using the linear interac-tion energy method. J Med Chem 46, 2074-2082.

[193] Rajamani R, Reynolds CH (2004) Modeling the protonationstates of the catalytic aspartates in beta-secretase. J MedChem 47, 5159-5166.

[194] Rajamani R, Reynolds CH (2004) Modeling the bindingaffinities of beta-secretase inhibitors: Application to subsitespecificity. Bioorg Med Chem Lett 14, 4843-4846.

[195] Tounge BA, Rajamani R, Baxter EW, Reitz AB, ReynoldsCH (2006) Linear interaction energy models for beta-secretase (BACE) inhibitors: Role of van der Waals,electrostatic, and continuum-solvation terms. J Mol GraphModel 24, 475-484.

[196] Baxter EW, Conway KA, Kennis L, Bischoff F, MerckenMH, Winter HL, Reynolds CH, Tounge BA, Luo C, ScottMK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, MasureS, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J,Alexander RS, Brenneman DE, Reitz AB (2007) 2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-siteAPP cleaving enzyme): Use of structure based design toconvert a micromolar hit into a nanomolar lead. J Med Chem50, 4261-4264.

[197] Huang Y, Strobel ED, Ho CY, Reynolds CH, Conway KA,Piesvaux JA, Brenneman DE, Yohrling GJ, Moore AH,Rosenthal D, Alexander RS, Tounge BA, Mercken M, Van-dermeeren M, Parker MH, Reitz AB, Baxter EW (2010)Macrocyclic BACE inhibitors: Optimization of a micro-molar hit to nanomolar leads. Bioorg Med Chem Lett 20,3158-3160.

[198] Lu Q, Chen WY, Zhu ZY, Chen J, Xu YC, Kaewpet M,Rukachaisirikul V, Chen LL, Shen X (2012) L655,240, act-ing as a competitive BACE1 inhibitor, efficiently decreasesbeta-amyloid peptide production in HEK293-APPswe cells.Acta Pharmacol Sin 33, 1459-1468.

[199] Lerchner A, Machauer R, Betschart C, Veenstra S, RueegerH, McCarthy C, Tintelnot-Blomley M, Jaton AL, Rabe S,Desrayaud S, Enz A, Staufenbiel M, Paganetti P, RondeauJM, Neumann U (2010) Macrocyclic BACE-1 inhibitorsacutely reduce Abeta in brain after po application. BioorgMed Chem Lett 20, 603-607.

[200] Rueeger H, Rondeau JM, McCarthy C, Mobitz H, Tintelnot-Blomley M, Neumann U, Desrayaud S (2011) Structurebased design, synthesis and SAR of cyclic hydroxyethy-lamine (HEA) BACE-1 inhibitors. Bioorg Med Chem Lett21, 1942-1947.

[201] Rueeger H, Lueoend R, Rogel O, Rondeau JM, MobitzH, Machauer R, Jacobson L, Staufenbiel M, Desrayaud S,Neumann U (2012) Discovery of cyclic sulfone hydrox-yethylamines as potent and selective beta-site APP-cleavingenzyme 1 (BACE1) inhibitors: Structure-based design andin vivo reduction of amyloid beta-peptides. J Med Chem 55,3364-3386.

[202] Rueeger H, Lueoend R, Machauer R, Veenstra SJ, JacobsonLH, Staufenbiel M, Desrayaud S, Rondeau JM, Mobitz H,Neumann U (2013) Discovery of cyclic sulfoxide hydrox-yethylamines as potent and selective beta-site APP-cleavingenzyme 1 (BACE1) inhibitors: Structure based design and invivo reduction of amyloid beta-peptides. Bioorg Med ChemLett 23, 5300-5306.

[203] Bowers S, Xu YZ, Yuan S, Probst GD, Hom RK, Chan W,Konradi AW, Sham HL, Zhu YL, Beroza P, Pan H, BrechtE, Yao N, Lougheed J, Tam D, Ren Z, Ruslim L, Bova MP,Artis DR (2013) Structure-based design of novel dihydroiso-quinoline BACE-1 inhibitors that do not engage the catalyticaspartates. Bioorg Med Chem Lett 23, 2181-2186.

[204] Xu YZ, Yuan S, Bowers S, Hom RK, Chan W, Sham HL, ZhuYL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Yan J,Tam D, Ren Z, Ruslim L, Bova MP, Artis DR (2013) Designand synthesis of thiophene dihydroisoquinolines as novelBACE1 inhibitors. Bioorg Med Chem Lett 23, 3075-3080.

[205] Ng RA, Sun M, Bowers S, Hom RK, Probst GD, John V,Fang LY, Maillard M, Gailunas A, Brogley L, Neitz RJ,Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS,Adler M, Yao N, Zmolek W, Nakamura D, Quinn KP, SauerJM, Bova MP, Ruslim L, Artis DR, Yednock TA (2013)Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Prime side chromane-containing inhibitors.Bioorg Med Chem Lett 23, 4674-4679.

[206] Efremov IV, Vajdos FF, Borzilleri KA, Capetta S, Chen H,Dorff PH, Dutra JK, Goldstein SW, Mansour M, McColl A,Noell S, Oborski CE, O’Connell TN, O’Sullivan TJ, Pan-dit J, Wang H, Wei B, Withka JM (2012) Discovery andoptimization of a novel spiropyrrolidine inhibitor of beta-secretase (BACE1) through fragment-based drug design. JMed Chem 55, 9069-9088.

[207] Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E,Murray J, Vajdos F, Ambroise C, Christoffersen C, FisherK, Lanyon L, Liu J, Nolan CE, Withka JM, BorzilleriKA, Efremov I, Oborski CE, Varghese A, O’Neill BT(2012) Spirocyclic sulfamides as beta-secretase 1 (BACE-1)inhibitors for the treatment of Alzheimer’s disease: Uti-lization of structure based drug design, WaterMap, andCNS penetration studies to identify centrally efficaciousinhibitors. J Med Chem 55, 9224-9239.

[208] Manzenrieder F, Frank AO, Huber T, Dorner-Ciossek C,Kessler H (2007) Synthesis and biological evaluation ofphosphino dipeptide isostere inhibitor of human beta-secretase (BACE1). Bioorg Med Chem 15, 4136-4143.

[209] Huber T, Manzenrieder F, Kuttruff CA, Dorner-CiossekC, Kessler H (2009) Prolonged stability by cyclization:Macrocyclic phosphino dipeptide isostere inhibitors of beta-secretase (BACE1). Bioorg Med Chem Lett 19, 4427-4431.

[210] Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, LiuY, Heise CE, Hoyte K, Luk W, Lu Y, Peng K, Wu P, RougeL, Zhang Y, Lazarus RA, Scearce-Levie K, Wang W, Wu Y,Tessier-Lavigne M, Watts RJ (2011) A therapeutic antibodytargeting BACE1 inhibits amyloid-beta production in vivo.Sci Transl Med 3, 84ra43.

[211] Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal J,Elliott JM, Prabhu S, Watts RJ, Dennis MS (2011) Boostingbrain uptake of a therapeutic antibody by reducing its affinityfor a transcytosis target. Sci Transl Med 3, 84ra44.

[212] Bien-Ly N, Yu YJ, Bumbaca D, Elstrott J, Boswell CA,Zhang Y, Luk W, Lu Y, Dennis MS, Weimer RM, Chung I,Watts RJ (2014) Transferrin receptor (TfR) trafficking deter-mines brain uptake of TfR antibody affinity variants. J ExpMed 211, 233-244.


[213] Couch JA, Yu YJ, Zhang Y, Tarrant JM, Fuji RN, MeilandtWJ, Solanoy H, Tong RK, Hoyte K, Luk W, Lu Y, GadkarK, Prabhu S, Ordonia BA, Nguyen Q, Lin Y, Lin Z, BalazsM, Scearce-Levie K, Ernst JA, Dennis MS, Watts RJ (2013)Addressing safety liabilities of TfR bispecific antibodies thatcross the blood-brain barrier. Sci Transl Med 5, 183ra57,1-183ra57,12.

[214] Barman A, Prabhakar R (2013) Elucidating the catalyticmechanism of beta-secretase (BACE1): A quantum mechan-ics/molecular mechanics (QM/MM) approach. J Mol GraphModel 40, 1-9.

[215] Yuan J, Venkatraman S, Zheng Y, McKeever BM, DillardLW, Singh SB (2013) Structure-based design of beta-siteAPP cleaving enzyme 1 (BACE1) inhibitors for the treat-ment of Alzheimer’s disease. J Med Chem 56, 4156-4180.

[216] Karpagam V, Sathishkumar N, Sathiyamoorthy S, Rasap-pan P, Shila S, Kim YJ, Yang DC (2013) Identification ofBACE1 inhibitors from Panax ginseng saponins-An Insilcoapproach. Comput Biol Med 43, 1037-1044.

[217] Cruz DS, Castilho MS (2014) 2D QSAR studies on series ofhuman beta-secretase (BACE-1) inhibitors. Med Chem 10,162-173.

[218] Kornacker MG, Lai Z, Witmer M, Ma J, Hendrick J, Lee VG,Riexinger DJ, Mapelli C, Metzler W, Copeland RA (2005)An inhibitor binding pocket distinct from the catalytic activesite on human beta-APP cleaving enzyme. Biochemistry 44,11567-11573.

[219] Iben LG, Kopcho L, Marcinkeviciene J, Zheng C, Thomp-son LA, Albright CF, Toyn JH (2008) [3H]BMS-599240–anovel tritiated ligand for the characterization of BACE1inhibitors. Eur J Pharmacol 593, 10-15.

[220] Wu YJ, Zhang Y, Good AC, Burton CR, Toyn JH,Albright CF, Macor JE, Thompson LA (2009) Synthesis andSAR of hydroxyethylamine based phenylcarboxyamides asinhibitors of BACE. Bioorg Med Chem Lett 19, 2654-2660.

[221] Marcin LR, Higgins MA, Zusi FC, Zhang Y, Dee MF, ParkerMF, Muckelbauer JK, Camac DM, Morin PE, RamamurthyV, Tebben AJ, Lentz KA, Grace JE, Marcinkeviciene JA,Kopcho LM, Burton CR, Barten DM, Toyn JH, Mered-ith JE, Albright CF, Bronson JJ, Macor JE, Thompson LA(2011) Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1.Bioorg Med Chem Lett 21, 537-541.

[222] Thompson LA, Shi J, Decicco CP, Tebben AJ, Olson RE,Boy KM, Guernon JM, Good AC, Liauw A, Zheng C,Copeland RA, Combs AP, Trainor GL, Camac DM, Muck-elbauer JK, Lentz KA, Grace JE, Burton CR, Toyn JH,Barten DM, Marcinkeviciene J, Meredith JE, Albright CF,Macor JE (2011) Synthesis and in vivo evaluation of cyclicdiaminopropane BACE-1 inhibitors. Bioorg Med Chem Lett21, 6909-6915.

[223] Boy KM, Guernon JM, Shi J, Toyn JH, Meredith JE, BartenDM, Burton CR, Albright CF, Marcinkeviciene J, GoodAC, Tebben AJ, Muckelbauer JK, Camac DM, Lentz KA,Bronson JJ, Olson RE, Macor JE, Thompson LA III (2011)Monosubstituted gamma-lactam and conformationally con-strained 1,3-diaminopropan-2-ol transition-state isostereinhibitors of beta-secretase (BACE). Bioorg Med Chem Lett21, 6916-6924.

[224] Gerritz SW, Zhai W, Shi S, Zhu S, Toyn JH, Meredith JEJr, Iben LG, Burton CR, Albright CF, Good AC, TebbenAJ, Muckelbauer JK, Camac DM, Metzler W, Cook LS,Padmanabha R, Lentz KA, Sofia MJ, Poss MA, Macor JE,Thompson LA III (2012) Acyl guanidine inhibitors of beta-secretase (BACE-1): Optimization of a micromolar hit to

a nanomolar lead via iterative solid- and solution-phaselibrary synthesis. J Med Chem 55, 9208-9223.

[225] Back M, Nyhlen J, Kvarnstrom I, Appelgren S, BorkakotiN, Jansson K, Lindberg J, Nystrom S, Hallberg A, Rosen-quist S, Samuelsson B (2008) Design, synthesis and SARof potent statine-based BACE-1 inhibitors: Exploration ofP1 phenoxy and benzyloxy residues. Bioorg Med Chem 16,9471-9486.

[226] Sund C, Belda O, Borkakoti N, Lindberg J, Derbyshire D,Vrang L, Hamelink E, Hgren C, Woestenenk E, WikstromK, Eneroth A, Lindstrom E, Kalayanov G (2012) Designand synthesis of potent hydroxyethylamine (HEA) BACE-1inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazoleand 4,5,6,7-tetrahydropyridinoazole templates. Bioorg MedChem Lett 22, 6721-6727.

[227] Charrier N, Clarke B, Cutler L, Demont E, Dingwall C,Dunsdon R, East P, Hawkins J, Howes C, Hussain I, Jef-frey P, Maile G, Matico R, Mosley J, Naylor A, O’BrienA, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S,Theobald P, Vesey D, Walter DS, Wayne G (2008) Secondgeneration of hydroxyethylamine BACE-1 inhibitors: Opti-mizing potency and oral bioavailability. J Med Chem 51,3313-3317.

[228] Charrier N, Clarke B, Cutler L, Demont E, Dingwall C,Dunsdon R, Hawkins J, Howes C, Hubbard J, HussainI, Maile G, Matico R, Mosley J, Naylor A, O’Brien A,Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S,Theobald P, Vesey D, Walter DS, Wayne G (2009) Sec-ond generation of BACE-1 inhibitors. Part 1: The needfor improved pharmacokinetics. Bioorg Med Chem Lett 19,3664-3668.

[229] Charrier N, Clarke B, Demont E, Dingwall C, DunsdonR, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R,Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland P,Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Wal-ter DS, Wayne G (2009) Second generation of BACE-1inhibitors part 2: Optimisation of the non-prime side sub-stituent. Bioorg Med Chem Lett 19, 3669-3673.

[230] Charrier N, Clarke B, Cutler L, Demont E, Dingwall C,Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain I,Maile G, Matico R, Mosley J, Naylor A, O’Brien A, Red-shaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, TheobaldP, Vesey D, Walter DS, Wayne G (2009) Second generationof BACE-1 inhibitors part 3: Towards non hydroxyethy-lamine transition state mimetics. Bioorg Med Chem Lett 19,3674-3678.

[231] Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cut-ler L, Buck T, Walter D, Demont E, Howes C, Naylor A,Jeffrey P, Gonzalez MI, Dingwall C, Michel A, Redshaw S,Davis JB (2007) Oral administration of a potent and selec-tive non-peptidic BACE-1 inhibitor decreases beta-cleavageof amyloid precursor protein and amyloid-beta productionin vivo. J Neurochem 100, 802-809.

[232] Beswick P, Charrier N, Clarke B, Demont E, Dingwall C,Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I,Johnson CN, MacPherson D, Maile G, Matico R, Milner P,Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Row-land P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G,Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, WardJ, Wayne G (2008) BACE-1 inhibitors part 3: Identificationof hydroxy ethylamines (HEAs) with nanomolar potency incells. Bioorg Med Chem Lett 18, 1022-1026.

[233] Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A,Hawkins J, Hussain I, MacPherson D, Maile G, MaticoR, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S,


Riddell D, Rowland P, Soleil V, Smith KJ, Stanway S, StempG, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J,Wayne G (2008) BACE-1 inhibitors part 1: Identification ofnovel hydroxy ethylamines (HEAs). Bioorg Med Chem Lett18, 1011-1016.

[234] Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A,Hawkins J, Hussain I, MacPherson D, Maile G, Matico R,Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Rid-dell D, Rowland P, Soleil V, Smith KJ, Stanway S, Stemp G,Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, WayneG (2008) BACE-1 inhibitors part 2: Identification of hydroxyethylamines (HEAs) with reduced peptidic character. BioorgMed Chem Lett 18, 1017-1021.

[235] Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R,Hawkins J, Howes C, Hussain I, Maile G, Matico R, MosleyJ, Naylor A, O’Brien A, Redshaw S, Rowland P, Soleil V,Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS,Wayne G (2010) BACE-1 hydroxyethylamine inhibitorsusing novel edge-to-face interaction with Arg-296. BioorgMed Chem Lett 20, 4639-4644.

[236] Hu J, Cwi CL, Smiley DL, Timm D, Erickson JA, McGeeJE, Yang HC, Mendel D, May PC, Shapiro M, McCarthy JR(2003) Design and synthesis of statine-containing BACEinhibitors. Bioorg Med Chem Lett 13, 4335-4339.

[237] Chen SH, Lamar J, Guo D, Kohn T, Yang HC, McGee J,Timm D, Erickson J, Yip Y, May P, McCarthy J (2004) P3cap modified Phe∗-Ala series BACE inhibitors. Bioorg MedChem Lett 14, 245-250.

[238] Lamar J, Hu J, Bueno AB, Yang HC, Guo D, Copp JD,McGee J, Gitter B, Timm D, May P, McCarthy J, Chen SH(2004) Phe*-Ala-based pentapeptide mimetics are BACEinhibitors: P2 and P3 SAR. Bioorg Med Chem Lett 14, 239-243.

[239] Vidal P, Timm D, Broughton H, Chen SH, Martin JA, Rivera-Sagredo A, McCarthy JR, Shapiro MJ, Espinosa JF (2005)Preorganization of the hydroxyethylene dipeptide isostere:The preferred conformation in solution resembles the con-formation bound to BACE. J Med Chem 48, 7623-7627.

[240] May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM,Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM,Stout SL, Timm DE, Smith LE, Gonzales CR, Nakano M,Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO,Cocke PJ, Greg HD, Friedrich S, Citron M, Audia JE (2011)Robust central reduction of amyloid-beta in humans withan orally available, non-peptidic beta-secretase inhibitor. JNeurosci 31, 16507-16516.

[241] Lahiri DK, Maloney B, Long JM, Greig NH (2014) Lessonsfrom a BACE1 inhibitor trial: Off-site but not off base.Alzheimers Dement, doi: 10.1016/j.jalz.2013.11.004

[242] Woltering TJ, Wostl W, Hilpert H, Rogers-Evans M, PinardE, Mayweg A, Gobel M, Banner DW, Benz J, Travagli M,Pollastrini M, Marconi G, Gabellieri E, Guba W, MauserH, Andreini M, Jacobsen H, Power E, Narquizian R (2013)BACE1 inhibitors: A head group scan on a series of amides.Bioorg Med Chem Lett 23, 4239-4243.

[243] Gruninger-Leitch F, Schlatter D, Kung E, Nelbock P, DobeliH (2002) Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian asparticproteases. J Biol Chem 277, 4687-4693.

[244] Kuglstatter A, Stahl M, Peters JU, Huber W, Stihle M,Schlatter D, Benz J, Ruf A, Roth D, Enderle T, Hennig M(2008) Tyramine fragment binding to BACE-1. Bioorg MedChem Lett 18, 1304-1307.

[245] Hu B, Fan KY, Bridges K, Chopra R, Lovering F, Cole D,Zhou P, Ellingboe J, Jin G, Cowling R, Bard J (2004) Syn-

thesis and SAR of bis-statine based peptides as BACE 1inhibitors. Bioorg Med Chem Lett 14, 3457-3460.

[246] Bridges KG, Chopra R, Lin L, Svenson K, Tam A, Jin G,Cowling R, Lovering F, Akopian TN, Blasio-Smith E, nnis-Freeman B, Marvell TH, LaVallie ER, Zollner RS, Bard J,Somers WS, Stahl ML, Kriz RW (2006) A novel approachto identifying beta-secretase inhibitors: Bis-statine peptidemimetics discovered using structure and spot synthesis. Pep-tides 27, 1877-1885.

[247] Cole DC, Manas ES, Stock JR, Condon JS, Jennings LD,Aulabaugh A, Chopra R, Cowling R, Ellingboe JW, FanKY, Harrison BL, Hu Y, Jacobsen S, Jin G, Lin L, LoveringFE, Malamas MS, Stahl ML, Strand J, Sukhdeo MN, Sven-son K, Turner MJ, Wagner E, Wu J, Zhou P, Bard J (2006)Acylguanidines as small-molecule beta-secretase inhibitors.J Med Chem 49, 6158-6161.

[248] Cole DC, Stock JR, Chopra R, Cowling R, Ellingboe JW,Fan KY, Harrison BL, Hu Y, Jacobsen S, Jennings LD, Jin G,Lohse PA, Malamas MS, Manas ES, Moore WJ, O’DonnellMM, Olland AM, Robichaud AJ, Svenson K, Wu J, WagnerE, Bard J (2008) Acylguanidine inhibitors of beta-secretase:Optimization of the pyrrole ring substituents extending intothe S1 and S3 substrate binding pockets. Bioorg Med ChemLett 18, 1063-1066.

[249] Fobare WF, Solvibile WR, Robichaud AJ, Malamas MS,Manas E, Turner J, Hu Y, Wagner E, Chopra R, CowlingR, Jin G, Bard J (2007) Thiophene substituted acylguani-dines as BACE1 inhibitors. Bioorg Med Chem Lett 17, 5353-5356.

[250] Freskos JN, Fobian YM, Benson TE, Bienkowski MJ,Brown DL, Emmons TL, Heintz R, Laborde A, McDon-ald JJ, Mischke BV, Molyneaux JM, Moon JB, MullinsPB, Bryan PD, Paddock DJ, Tomasselli AG, Winterrowd G(2007) Design of potent inhibitors of human beta-secretase.Part 1. Bioorg Med Chem Lett 17, 73-77.

[251] Freskos JN, Fobian YM, Benson TE, Moon JB, BienkowskiMJ, Brown DL, Emmons TL, Heintz R, Laborde A, McDon-ald JJ, Mischke BV, Molyneaux JM, Mullins PB, Bryan PD,Paddock DJ, Tomasselli AG, Winterrowd G (2007) Designof potent inhibitors of human beta-secretase. Part 2. BioorgMed Chem Lett 17, 78-81.

[252] Kortum SW, Benson TE, Bienkowski MJ, Emmons TL,Prince DB, Paddock DJ, Tomasselli AG, Moon JB, LabordeA, TenBrink RE (2007) Potent and selective isophthalamideS2 hydroxyethylamine inhibitors of BACE1. Bioorg MedChem Lett 17, 3378-3383.

[253] Jennings LD, Cole DC, Stock JR, Sukhdeo MN, EllingboeJW, Cowling R, Jin G, Manas ES, Fan KY, Malamas MS,Harrison BL, Jacobsen S, Chopra R, Lohse PA, Moore WJ,O’Donnell MM, Hu Y, Robichaud AJ, Turner MJ, WagnerE, Bard J (2008) Acylguanidine inhibitors of beta-secretase:Optimization of the pyrrole ring substituents extending intothe S1’ substrate binding pocket. Bioorg Med Chem Lett 18,767-771.

[254] Malamas MS, Erdei J, Gunawan I, Barnes K, Johnson M,Hui Y, Turner J, Hu Y, Wagner E, Fan K, Olland A, Bard J,Robichaud AJ (2009) Aminoimidazoles as potent and selec-tive human beta-secretase (BACE1) inhibitors. J Med Chem52, 6314-6323.

[255] Malamas MS, Erdei J, Gunawan I, Turner J, Hu Y, WagnerE, Fan K, Chopra R, Olland A, Bard J, Jacobsen S, MagoldaRL, Pangalos M, Robichaud AJ (2010) Design and synthesisof 5,5’-disubstituted aminohydantoins as potent and selec-tive human beta-secretase (BACE1) inhibitors. J Med Chem53, 1146-1158.


[256] Malamas MS, Barnes K, Johnson M, Hui Y, Zhou P,Turner J, Hu Y, Wagner E, Fan K, Chopra R, Olland A,Bard J, Pangalos M, Reinhart P, Robichaud AJ (2010) Di-substituted pyridinyl aminohydantoins as potent and highlyselective human beta-secretase (BACE1) inhibitors. BioorgMed Chem 18, 630-639.

[257] Malamas MS, Barnes K, Hui Y, Johnson M, LoveringF, Condon J, Fobare W, Solvibile W, Turner J, Hu Y,Manas ES, Fan K, Olland A, Chopra R, Bard J, Panga-los MN, Reinhart P, Robichaud AJ (2010) Novel pyrrolyl2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors. Bioorg Med Chem Lett 20,2068-2073.

[258] Malamas MS, Robichaud A, Erdei J, Quagliato D, Solvi-bile W, Zhou P, Morris K, Turner J, Wagner E, Fan K,Olland A, Jacobsen S, Reinhart P, Riddell D, Pangalos M(2010) Design and synthesis of aminohydantoins as potentand selective human beta-secretase (BACE1) inhibitors withenhanced brain permeability. Bioorg Med Chem Lett 20,6597-6605.

[259] Malamas MS, Erdei J, Gunawan I, Barnes K, Hui Y, JohnsonM, Robichaud A, Zhou P, Yan Y, Solvibile W, Turner J, FanKY, Chopra R, Bard J, Pangalos MN (2011) New pyrazolyland thienyl aminohydantoins as potent BACE1 inhibitors:Exploring the S2’ region. Bioorg Med Chem Lett 21, 5164-5170.

[260] Nowak P, Cole DC, Aulabaugh A, Bard J, Chopra R, Cowl-ing R, Fan KY, Hu B, Jacobsen S, Jani M, Jin G, LoMC, Malamas MS, Manas ES, Narasimhan R, Reinhart P,Robichaud AJ, Stock JR, Subrath J, Svenson K, Turner J,Wagner E, Zhou P, Ellingboe JW (2010) Discovery andinitial optimization of 5,5’-disubstituted aminohydantoinsas potent beta-secretase (BACE1) inhibitors. Bioorg MedChem Lett 20, 632-635.

[261] Zhou P, Li Y, Fan Y, Wang Z, Chopra R, Olland A, Hu Y,Magolda RL, Pangalos M, Reinhart PH, Turner MJ, BardJ, Malamas MS, Robichaud AJ (2010) Pyridinyl aminohy-dantoins as small molecule BACE1 inhibitors. Bioorg MedChem Lett 20, 2326-2329.

[262] Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, DeSB, Steiner H, Haass C, Wolfe MS (2007) Active gamma-secretase complexes contain only one of each component. JBiol Chem 282, 33985-33993.

[263] Wolfe MS (2012) gamma-Secretase inhibitors and modu-lators for Alzheimer’s disease. J Neurochem 120(Suppl 1),89-98.

[264] Barthet G, Georgakopoulos A, Robakis NK (2012) Cel-lular mechanisms of gamma-secretase substrate selection,processing and toxicity. Prog Neurobiol 98, 166-175.

[265] Golde TE, Koo EH, Felsenstein KM, Osborne BA, MieleL (2013) gamma-Secretase inhibitors and modulators.Biochim Biophys Acta 1828, 2898-2907.

[266] Ran Y, Cruz PE, Ladd TB, Fauq AH, Jung JI, MatthewsJ, Felsenstein KM, Golde TE (2014) gamma-Secretaseprocessing and effects of gamma-secretase inhibitors andmodulators on long Abeta peptides in cells. J Biol Chem289, 3276-3287.

[267] Hou Y, Yu YB, Liu G, Luo Y (2009) A natu-ral squamosamide derivative FLZ reduces amyloid-betaproduction by increasing non-amyloidogenic AbetaPP pro-cessing. J Alzheimers Dis 18, 153-165.

[268] Ye X, Tai W, Bao X, Chen X, Zhang D (2014) FLZinhibited gamma-secretase selectively and decreased Abetamitochondrial production in APP-SH-SY5Y cells. NaunynSchmiedebergs Arch Pharmacol 387, 75-85.

[269] Augelli-Szafran CE, Wei HX, Lu D, Zhang J, Gu Y, Yang T,Osenkowski P, Ye W, Wolfe MS (2010) Discovery of notch-sparing gamma-secretase inhibitors. Curr Alzheimer Res 7,207-209.

[270] Stepan AF, Subramanyam C, Efremov IV, Dutra JK,O’Sullivan TJ, Dirico KJ, McDonald WS, Won A, DorffPH, Nolan CE, Becker SL, Pustilnik LR, Riddell DR,Kauffman GW, Kormos BL, Zhang L, Lu Y, Capetta SH,Green ME, Karki K, Sibley E, Atchison KP, Hallgren AJ,Oborski CE, Robshaw AE, Sneed B, O’Donnell CJ (2012)Application of the bicyclo[1.1.1]pentane motif as a nonclas-sical phenyl ring bioisostere in the design of a potent andorally active gamma-secretase inhibitor. J Med Chem 55,3414-3424.

[271] Takagi-Niidome S, Osawa S, Tomita T, Iwatsubo T (2013)Inhibition of gamma-secretase activity by a monoclonalantibody against the extracellular hydrophilic loop of pre-senilin 1. Biochemistry 52, 61-69.

[272] Tong G, Wang JS, Sverdlov O, Huang SP, SlemmonR, Croop R, Castaneda L, Gu H, Wong O, Li H,Berman RM, Smith C, Albright CF, Dockens RC (2012)Multicenter, randomized, double-blind, placebo-controlled,single-ascending dose study of the oral gamma-secretaseinhibitor BMS-708163 (Avagacestat): Tolerability profile,pharmacokinetic parameters, and pharmacodynamic mark-ers. Clin Ther 34, 654-667.

[273] Coric V, van Dyck CH, Salloway S, Andreasen N, BrodyM, Richter RW, Soininen H, Thein S, Shiovitz T, PilcherG, Colby S, Rollin L, Dockens R, Pachai C, Portelius E,Andreasson U, Blennow K, Soares H, Albright C, Feld-man HH, Berman RM (2012) Safety and tolerability of thegamma-secretase inhibitor avagacestat in a phase 2 studyof mild to moderate Alzheimer disease. Arch Neurol 69,1430-1440.

[274] Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP,Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C,Albright CF, Tong G (2012) A placebo-controlled, multipleascending dose study to evaluate the safety, pharmacokinet-ics and pharmacodynamics of avagacestat (BMS-708163)in healthy young and elderly subjects. Clin Pharmacokinet51, 681-693.

[275] Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R,Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM,Smith C, Albright CF, Dockens R (2013) A contrast insafety, pharmacokinetics and pharmacodynamics across agegroups after a single 50mg oral dose of the gamma-secretaseinhibitor avagacestat. Br J Clin Pharmacol 75, 136-145.

[276] Gu H, Deng Y, Wang J, Aubry AF, Arnold ME (2010)Development and validation of sensitive and selective LC-MS/MS methods for the determination of BMS-708163,a gamma-secretase inhibitor, in plasma and cerebrospinalfluid using deprotonated or formate adduct ions as precur-sor ions. J Chromatogr B Analyt Technol Biomed Life Sci878, 2319-2326.

[277] Prasad CV, Wallace OB, Noonan JW, Sloan CP, Lau W, VigS, Parker MF, Smith DW, Hansel SB, Polson CT, Barten DM,Felsenstein KM, Roberts SB (2004) Hydroxytriamides aspotent gamma-secretase inhibitors. Bioorg Med Chem Lett14, 1917-1921.

[278] Prasad CV, Vig S, Smith DW, Gao Q, Polson CT, CorsaJA, Guss VL, Loo A, Barten DM, Zheng M, FelsensteinKM, Roberts SB (2004) 2,3-Benzodiazepin-1,4-diones aspeptidomimetic inhibitors of gamma-secretase. Bioorg MedChem Lett 14, 3535-3538.


[279] Prasad CV, Zheng M, Vig S, Bergstrom C, Smith DW,Gao Q, Yeola S, Polson CT, Corsa JA, Guss VL, LooA, Wang J, Sleczka BG, Dangler C, Robertson BJ,Hendrick JP, Roberts SB, Barten DM (2007) Discovery of(S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): A gamma-secretaseinhibitor with Abeta lowering activity in a transgenicmouse model of Alzheimer’s disease. Bioorg Med ChemLett 17, 4006-4011.

[280] Yan XX, Li T, Rominger CM, Prakash SR, Wong PC, OlsonRE, Zaczek R, Li YW (2004) Binding sites of gamma-secretase inhibitors in rodent brain: Distribution, postnataldevelopment, and effect of deafferentation. J Neurosci 24,2942-2952.

[281] Thompson LA, Liauw AY, Ramanjulu MM, Kasireddy-Polam P, Mercer SE, Maduskuie TP, Glicksman M, RoachAH, Meredith JE, Liu RQ, Combs AP, Higaki JN, CordellB, Seiffert D, Zaczek RC, Robertson DW, Olson RE(2006) Synthesis and evaluation of succinoyl-caprolactamgamma-secretase inhibitors. Bioorg Med Chem Lett 16,2357-2363.

[282] Parker MF, Barten DM, Bergstrom CP, Bronson JJ, CorsaJA, Deshpande MS, Felsenstein KM, Guss VL, Hansel SB,Johnson G, Keavy DJ, Lau WY, Mock J, Prasad CV, PolsonCT, Sloan CP, Smith DW, Wallace OB, Wang HH, WilliamsA, Zheng M (2007) N-(5-chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as gamma-secretase inhibitors.Bioorg Med Chem Lett 17, 4432-4436.

[283] Parker MF, Bronson JJ, Barten DM, Corsa JA, Du W,Felsenstein KM, Guss VL, Izzarelli D, Loo A, McElhoneKE, Marcin LR, Padmanabha R, Pak R, Polson CT, ToynJH, Varma S, Wang J, Wong V, Zheng M, Roberts SB(2007) Amino-caprolactam derivatives as gamma-secretaseinhibitors. Bioorg Med Chem Lett 17, 5790-5795.

[284] Yang MG, Shi JL, Modi DP, Wells J, Cochran BM, WolfMA, Thompson LA, Ramanjulu MM, Roach AH, ZaczekR, Robertson DW, Wexler RR, Olson RE (2007) Design andsynthesis of benzoazepinone-derived cyclic malonamidesand aminoamides as potent gamma-secretase inhibitors.Bioorg Med Chem Lett 17, 3910-3915.

[285] Bergstrom CP, Sloan CP, Wang HH, Parker MF, Smith DW,Zheng M, Hansel SB, Polson CT, Barber LE, Bursuker I,Guss VL, Corsa JA, Barten DM, Felsenstein KM, RobertsSB (2008) Nitrogen-appended N-alkylsulfonamides asinhibitors of gamma-secretase. Bioorg Med Chem Lett 18,175-178.

[286] Bergstrom CP, Sloan CP, Lau WY, Smith DW, ZhengM, Hansel SB, Polson CT, Corsa JA, Barten DM,Felsenstein KM, Roberts SB (2008) Carbamate-appendedN-alkylsulfonamides as inhibitors of gamma-secretase.Bioorg Med Chem Lett 18, 464-468.

[287] Gillman KW, Starrett JE, Parker MF, Xie K, BronsonJJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA,Williams R, Meredith JE, Burton CR, Barten DM, Toyn JH,Roberts SB, Lentz KA, Houston JG, Zaczek R, AlbrightCF, Decicco CP, Macor JE, Olson RE (2010) Discovery andevaluation of BMS-708163, a potent, selective and orallybioavailable gamma-secretase inhibitor. ACS Med ChemLett 1, 120-124.

[288] Panza F, Frisardi V, Imbimbo BP, Capurso C, LogroscinoG, Sancarlo D, Seripa D, Vendemiale G, Pilotto A, Sol-frizzi V (2010) REVIEW: Gamma-Secretase inhibitors forthe treatment of Alzheimer’s disease: The current state. CNSNeurosci Ther 16, 272-284.

[289] Albright CF, Dockens RC, Meredith JE Jr, Olson RE,Slemmon R, Lentz KA, Wang JS, Denton RR, PilcherG, Rhyne PW, Raybon JJ, Barten DM, Burton C, ToynJH, Sankaranarayanan S, Polson C, Guss V, White R,Simutis F, Sanderson T, Gillman KW, Starrett JE Jr, Bron-son J, Sverdlov O, Huang SP, Castaneda L, Feldman H,Coric V, Zaczek R, Macor JE, Houston J, Berman RM,Tong G (2013) Pharmacodynamics of selective inhibitionof gamma-secretase by avagacestat. J Pharmacol Exp Ther344, 686-695.

[290] Nakano-Ito K, Fujikawa Y, Hihara T, Shinjo H, Kotani S,Suganuma A, Aoki T, Tsukidate K (2014) E2012-inducedcataract and its predictive biomarkers. Toxicol Sci 137, 249-258.

[291] Churcher I, Beher D, Best JD, Castro JL, Clarke EE,Gentry A, Harrison T, Hitzel L, Kay E, Kerrad S, LewisHD, Morentin-Gutierrez P, Mortishire-Smith R, Oakley PJ,Reilly M, Shaw DE, Shearman MS, Teall MR, WilliamsS, Wrigley JD (2006) 4-substituted cyclohexyl sulfonesas potent, orally active gamma-secretase inhibitors. BioorgMed Chem Lett 16, 280-284.

[292] Josien H, Bara T, Rajagopalan M, Asberom T, Clader JW,Favreau L, Greenlee WJ, Hyde LA, Nomeir AA, ParkerEM, Pissarnitski DA, Song L, Wong GT, Zhang L, ZhangQ, Zhao Z (2007) Small conformationally restricted piperi-dine N-arylsulfonamides as orally active gamma-secretaseinhibitors. Bioorg Med Chem Lett 17, 5330-5335.

[293] Josien H, Bara T, Rajagopalan M, Clader JW, Greenlee WJ,Favreau L, Hyde LA, Nomeir AA, Parker EM, Song L,Zhang L, Zhang Q (2009) Novel orally active morpholine N-arylsulfonamides gamma-secretase inhibitors with low CYP3A4 liability. Bioorg Med Chem Lett 19, 6032-6037.

[294] Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T,Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL (2000)L-685,458, an aspartyl protease transition state mimic, is apotent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 39, 8698-8704.

[295] Nadin A, Sanchez Lopez JM, Neduvelil JG, Thomas SR(2001) A stereocontrolled synthesis of 2R-benzyl-5S-tert-butoxycarbonyl-amino-4R-(tert-butyldimethylsilanyloxy)-6-phenyl-hexanoic acid (Phe-Phe hydroxy-ethylenedipeptide isostere). Tetrahedron 57, 1861-1864.

[296] Nadin A, Owens AP, Castro JL, Harrison T, ShearmanMS (2003) Synthesis and gamma-secretase activity of APPsubstrate-based hydroxyethylene dipeptide isosteres. BioorgMed Chem Lett 13, 37-41.

[297] Xu M, Lai MT, Huang Q, Muzio-Mower J, Castro JL, Har-rison T, Nadin A, Neduvelil JG, Shearman MS, ShaferJA, Gardell SJ, Li YM (2002) gamma-Secretase: Charac-terization and implication for Alzheimer disease therapy.Neurobiol Aging 23, 1023-1030.

[298] Churcher I, Ashton K, Butcher JW, Clarke EE, Harri-son T, Lewis HD, Owens AP, Teall MR, Williams S,Wrigley JD (2003) A new series of potent benzodiazepinegamma-secretase inhibitors. Bioorg Med Chem Lett 13,179-183.

[299] Churcher I, Williams S, Kerrad S, Harrison T, CastroJL, Shearman MS, Lewis HD, Clarke EE, Wrigley JD,Beher D, Tang YS, Liu W (2003) Design and synthesis ofhighly potent benzodiazepine gamma-secretase inhibitors:Preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-N-((3S)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1H-benzo[e][1, 4]-diazepin-3-yl)butyramide byuse of an asymmetric Ireland-Claisen rearrangement. J MedChem 46, 2275-2278.


[300] Scott JP, Lieberman DR, Beureux OM, Brands KM, DaviesAJ, Gibson AW, Hammond DC, McWilliams CJ, StewartGW, Wilson RD, Dolling UH (2007) A practical synthesisof a gamma-secretase inhibitor. J Org Chem 72, 4149-4155.

[301] Owens AP, Nadin A, Talbot AC, Clarke EE, HarrisonT, Lewis HD, Reilly M, Wrigley JD, Castro JL (2003)High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors. Bioorg Med Chem Lett13, 4143-4145.

[302] Lewis SJ, Smith AL, Neduvelil JG, Stevenson GI, LindonMJ, Jones AB, Shearman MS, Beher D, Clarke E, Best JD,Peachey JE, Harrison T, Castro JL (2005) A novel seriesof potent gamma-secretase inhibitors based on a benzobi-cyclo[4.2.1]nonane core. Bioorg Med Chem Lett 15, 373-378.

[303] Sparey T, Beher D, Best J, Biba M, Castro JL, Clarke E,Hannam J, Harrison T, Lewis H, Madin A, Shearman M,Sohal B, Tsou N, Welch C, Wrigley J (2005) Cyclic sul-famide gamma-secretase inhibitors. Bioorg Med Chem Lett15, 4212-4216.

[304] Sparey T, Clarke E, Hannam J, Harrison T, Madin A,Shearman M, Sohal B (2008) Sulfonamide derivatives ofbridgehead substituted bicyclo[4.2.1]nonanes as gamma-secretase inhibitors. Bioorg Med Chem Lett 18, 375-379.

[305] Jelley RA, Elliott J, Gibson KR, Harrison T, BeherD, Clarke EE, Lewis HD, Shearman M, Wrigley JD(2006) 3-Substituted gem-cyclohexane sulfone basedgamma-secretase inhibitors for Alzheimer’s disease: Con-formational analysis and biological activity. Bioorg MedChem Lett 16, 3839-3842.

[306] Scott JP, Oliver SF, Brands KM, Brewer SE, Davies AJ,Gibb AD, Hands D, Keen SP, Sheen FJ, Reamer RA, WilsonRD, Dolling UH (2006) Practical asymmetric synthesis ofa gamma-secretase inhibitor exploiting substrate-controlledintramolecular nitrile oxide-olefin cycloaddition. J OrgChem 71, 3086-3092.

[307] Shaw D, Best J, Dinnell K, Nadin A, Shearman M, PattisonC, Peachey J, Reilly M, Williams B, Wrigley J, Harrison T(2006) 3,4-Fused cyclohexyl sulfones as gamma-secretaseinhibitors. Bioorg Med Chem Lett 16, 3073-3077.

[308] Davies AJ, Scott JP, Bishop BC, Brands KM, Brewer SE,Dasilva JO, Dormer PG, Dolling UH, Gibb AD, Ham-mond DC, Lieberman DR, Palucki M, Payack JF (2007)A novel crystallization-induced diastereomeric transforma-tion based on a reversible carbon-sulfur bond formation.Application to the synthesis of a gamma-secretase inhibitor.J Org Chem 72, 4864-4871.

[309] Keown LE, Collins I, Cooper LC, Harrison T, Madin A,Mistry J, Reilly M, Shaimi M, Welch CJ, Clarke EE, LewisHD, Wrigley JD, Best JD, Murray F, Shearman MS (2009)Novel orally bioavailable gamma-secretase inhibitors withexcellent in vivo activity. J Med Chem 52, 3441-3444.

[310] Sasikumar TK, Qiang L, Burnett DA, Cole D, Xu R, LiH, Greenlee WJ, Clader J, Zhang L, Hyde L (2010) Tri-cyclic sulfones as orally active gamma-secretase inhibitors:Synthesis and structure-activity relationship studies. BioorgMed Chem Lett 20, 3632-3635.

[311] Sasikumar TK, Burnett DA, Asberom T, Wu WL, BennettC, Cole D, Xu R, Greenlee WJ, Clader J, Zhang L, HydeL (2010) Tetracyclic sulfones as potent gamma-secretaseinhibitors: Synthesis and structure-activity relationshipstudies. Bioorg Med Chem Lett 20, 3645-3648.

[312] Li H, Xu R, Cole D, Clader JW, Greenlee WJ, Nomeir AA,Song L, Zhang L (2010) Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines

as gamma-secretase inhibitors. Bioorg Med Chem Lett 20,6606-6609.

[313] Lee J, Song L, Terracina G, Bara T, Josien H, Asberom T,Sasikumar TK, Burnett DA, Clader J, Parker EM, ZhangL (2011) Identification of presenilin 1-selective gamma-secretase inhibitors with reconstituted gamma-secretasecomplexes. Biochemistry 50, 4973-4980.

[314] Wu WL, Asberom T, Bara T, Bennett C, Burnett DA,Clader J, Domalski M, Greenlee WJ, Josien H, McBriar M,Rajagopalan M, Vicarel M, Xu R, Hyde LA, Del VecchioRA, Cohen-Williams ME, Song L, Lee J, Terracina G, ZhangQ, Nomeir A, Parker EM, Zhang L (2013) Structure activityrelationship studies of tricyclic bispyran sulfone gamma-secretase inhibitors. Bioorg Med Chem Lett 23, 844-849.

[315] Wu WL, Sasikumar TK, Domalski MS, Qiang L, BurnettDA, Clader J, Greenlee WJ, Chan TM, Lee J, Zhang L (2013)A-ring modification of SCH 900229 and related chromenesulfone gamma-secretase inhibitors. Bioorg Med Chem Lett23, 850-853.

[316] Bai F, Tagen M, Colotta C, Miller L, Fouladi M, StewartCF (2010) Determination of the gamma-secretase inhibitorMK-0752 in human plasma by online extraction and elec-trospray tandem mass spectrometry (HTLC-ESI-MS/MS).J Chromatogr B Analyt Technol Biomed Life Sci 878, 2348-2352.

[317] Best JD, Smith DW, Reilly MA, O’Donnell R, Lewis HD,Ellis S, Wilkie N, Rosahl TW, Laroque PA, Boussiquet-Leroux C, Churcher I, Atack JR, Harrison T, ShearmanMS (2007) The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohe-xyl]-1,1, 1-trifluoromethanesulfonamide (MRK-560)reduces amyloid plaque deposition without evidence ofnotch-related pathology in the Tg2576 mouse. J PharmacolExp Ther 320, 552-558.

[318] Best JD, Jay MT, Otu F, Churcher I, Reilly M, Morentin-Gutierrez P, Pattison C, Harrison T, Shearman MS, Atack JR(2006) In vivo characterization of Abeta(40) changesin brain and cerebrospinal fluid using the novel gamma-secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1, 1-trifluoromethanesulfonamide (MRK-560) in the rat. J Pharmacol Exp Ther317, 786-790.

[319] Townsend M, Qu Y, Gray A, Wu Z, Seto T, Hutton M,Shearman MS, Middleton RE (2010) Oral treatment witha gamma-secretase inhibitor improves long-term potentia-tion in a mouse model of Alzheimer’s disease. J PharmacolExp Ther 333, 110-119.

[320] Li H, Asberom T, Bara TA, Clader JW, Greenlee WJ, JosienHB, McBriar MD, Nomeir A, Pissarnitski DA, RajagopalanM, Xu R, Zhao Z, Song L, Zhang L (2007) Discovery of2,4,6-trisubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors. Bioorg Med Chem Lett 17, 6290-6294.

[321] Pissarnitski DA, Asberom T, Bara TA, Buevich AV, CladerJW, Greenlee WJ, Guzik HS, Josien HB, Li W, McEwan M,McKittrick BA, Nechuta TL, Parker EM, Sinning L, SmithEM, Song L, Vaccaro HA, Voigt JH, Zhang L, Zhang Q,Zhao Z (2007) 2,6-Disubstituted N-arylsulfonyl piperidinesas gamma-secretase inhibitors. Bioorg Med Chem Lett 17,57-62.

[322] McBriar MD, Clader JW, Chu I, Del Vecchio RA, FavreauL, Greenlee WJ, Hyde LA, Nomeir AA, Parker EM, Pissar-nitski DA, Song L, Zhang L, Zhao Z (2008) Discovery ofamide and heteroaryl isosteres as carbamate replacements ina series of orally active gamma-secretase inhibitors. BioorgMed Chem Lett 18, 215-219.


[323] Vaccaro HA, Zhao Z, Clader JW, Song L, Terracina G, ZhangL, Pissarnitski DA (2008) Solution-phase parallel synthesisof carbamates as gamma-secretase inhibitors. J Comb Chem10, 56-62.

[324] Xu R, Cole D, Asberom T, Bara T, Bennett C, BurnettDA, Clader J, Domalski M, Greenlee W, Hyde L, JosienH, Li H, McBriar M, McKittrick B, McPhail AT, Pissarnit-ski D, Qiang L, Rajagopalan M, Sasikumar T, Su J, TangH, Wu WL, Zhang L, Zhao Z (2010) Design and synthe-sis of tricyclic sulfones as gamma-secretase inhibitors withgreatly reduced Notch toxicity. Bioorg Med Chem Lett 20,2591-2596.

[325] Su J, Tang H, McKittrick BA, Xu R, Clader JW, GreenleeWJ, Hyde L, Zhang L (2011) Synthesis and SAR study oftricyclic sulfones as gamma-secretase inhibitors: C-6 andC-8 positions. Bioorg Med Chem Lett 21, 3447-3451.

[326] Sun ZY, Asberom T, Bara T, Bennett C, Burnett D, Chu I,Clader J, Cohen-Williams M, Cole D, Czarniecki M, DurkinJ, Gallo G, Greenlee W, Josien H, Huang X, Hyde L, JonesN, Kazakevich I, Li H, Liu X, Lee J, Maccoss M, Man-dal MB, McCracken T, Nomeir A, Mazzola R, Palani A,Parker EM, Pissarnitski DA, Qin J, Song L, Terracina G,Vicarel M, Voigt J, Xu R, Zhang L, Zhang Q, Zhao Z, ZhuX, Zhu Z (2012) Cyclic hydroxyamidines as amide isosteres:Discovery of oxadiazolines and oxadiazines as potent andhighly efficacious gamma-secretase modulators in vivo. JMed Chem 55, 489-502.

[327] Close J, Heidebrecht R Jr, Hendrix J, Li C, Munoz B, Surdi L,Kattar S, Tempest P, Moses P, Geng X, Hughes B, SmotrovN, Moxham C, Chapnick J, Kariv I, Nikov G, Burke JE,Deshmukh S, Jeliazkova-Mecheva V, Leach JK, Diaz D, XuL, Yang Z, Kwei G, Moy L, Shah S, Tanga F, Kenefic C, Sav-age D, Shearman M, Ball RG, McNevin MJ, Markarewicz A,Miller T (2012) Lead optimization of 4,4-biaryl piperidineamides as gamma-secretase inhibitors. Bioorg Med ChemLett 22, 3203-3207.

[328] Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL,Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE,Brown TM, Finley JE, Sokolowski SA, Hicks CD, CoffmanKJ, Geoghegan KF, Brodney MA, Liston D, Tate B (2010)Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther 334,269-277.

[329] Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A,Tsaparikos K, Jani JP, Hosea N, Sands M, Randolph S,Smeal T (2010) Evaluation of selective gamma-secretaseinhibitor PF-03084014 for its antitumor efficacy and gas-trointestinal safety to guide optimal clinical trial design. MolCancer Ther 9, 1618-1628.

[330] Brodney MA, Auperin DD, Becker SL, Bronk BS, BrownTM, Coffman KJ, Finley JE, Hicks CD, Karmilowicz MJ,Lanz TA, Liston D, Liu X, Martin BA, Nelson RB, NolanCE, Oborski CE, Parker CP, Richter KE, Pozdnyakov N,Sahagan BG, Schachter JB, Sokolowski SA, Tate B, VanDeusen JW, Wood DE, Wood KM (2011) Diamide amino-imidazoles: A novel series of gamma-secretase inhibitorsfor the treatment of Alzheimer’s disease. Bioorg Med ChemLett 21, 2631-2636.

[331] Samon JB, Castillo-Martin M, Hadler M, mbesi-ImpiobatoA, Paietta E, Racevskis J, Wiernik PH, Rowe JM, JakubczakJ, Randolph S, Cordon-Cardo C, Ferrando AA (2012)Preclinical Analysis of the gamma-Secretase Inhibitor PF-03084014 in Combination with Glucocorticoids in T-cellAcute Lymphoblastic Leukemia. Mol Cancer Ther 11, 1565-1575.

[332] Pozdnyakov N, Murrey HE, Crump CJ, Pettersson M,Ballard TE, Am Ende CW, Ahn K, Li YM, Bales KR,Johnson DS (2013) gamma-Secretase modulator (GSM)photoaffinity probes reveal distinct allosteric binding siteson presenilin. J Biol Chem 288, 9710-9720.

[333] Dimitrov M, Alattia JR, Lemmin T, Lehal R, FligierA, Houacine J, Hussain I, Radtke F, Dal PM, BeherD, Fraering PC (2013) Alzheimer’s disease mutations inAPP but not gamma-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun 4,2246.

[334] Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU,Bulic B, Weggen S (2012) Presenilin is the molecular targetof acidic gamma-secretase modulators in living cells. PLoSOne 7, e30484.

[335] Wagner SL, Tanzi RE, Mobley WC, Galasko D (2012)Potential use of gamma-secretase modulators in the treat-ment of Alzheimer disease. Arch Neurol 69, 1255-1258.

[336] Xia W, Wong ST, Hanlon E, Morin P (2012) gamma-Secretase modulator in Alzheimer’s disease: Shifting theend. J Alzheimers Dis 31, 685-696.

[337] Pettersson M, Stepan AF, Kauffman GW, Johnson DS(2013) Novel gamma-secretase modulators for the treatmentof Alzheimer’s disease: A review focusing on patents from2010 to 2012. Expert Opin Ther Pat 23, 1349-1366.

[338] Jung JI, Ladd TB, Kukar T, Price AR, Moore BD, KooEH, Golde TE, Felsenstein KM (2013) Steroids as gamma-secretase modulators. FASEB J 27, 3775-3785.

[339] Hall A, Patel TR (2014) gamma-Secretase modulators:Current status and future directions. Prog Med Chem 53,101-145.

[340] Sivilia S, Lorenzini L, Giuliani A, Gusciglio M, FernandezM, Baldassarro VA, Mangano C, Ferraro L, Pietrini V, BarocMF, Viscomi AR, Ottonello S, Villetti G, Imbimbo BP, CalzaL, Giardino L (2013) Multi-target action of the novel anti-Alzheimer compound CHF5074: In vivo study of long termtreatment in Tg2576 mice. BMC Neurosci 14, 44.

[341] Giuliani A, Beggiato S, Baldassarro VA, Mangano C, Gia-rdino L, Imbimbo BP, Antonelli T, Calza L, Ferraro L (2013)CHF5074 restores visual memory ability and pre-synapticcortical acetylcholine release in pre-plaque Tg2576 mice. JNeurochem 124, 613-620.

[342] Branca C, Sarnico I, Ruotolo R, Lanzillotta A, Viscomi AR,Benarese M, Porrini V, Lorenzini L, Calza L, Imbimbo BP,Ottonello S, Pizzi M (2014) Pharmacological targeting ofthe beta-amyloid precursor protein intracellular domain. SciRep 4, 4618.

[343] Ross J, Sharma S, Winston J, Nunez M, Bottini G,Franceschi M, Scarpini E, Frigerio E, Fiorentini F, Fernan-dez M, Sivilia S, Giardino L, Calza L, Norris D, Cicirello H,Casula D, Imbimbo BP (2013) CHF5074 reduces biomark-ers of neuroinflammation in patients with mild cognitiveimpairment: A 12-week, double-blind, placebo- controlledstudy. Curr Alzheimer Res 10, 742-753.

[344] Rogers K, Felsenstein KM, Hrdlicka L, Tu Z, Albayya F,Lee W, Hopp S, Miller MJ, Spaulding D, Yang Z, Hodg-don H, Nolan S, Wen M, Costa D, Blain JF, Freeman E,De SB, Vulsteke V, Scrocchi L, Zetterberg H, Portelius E,Hutter-Paier B, Havas D, Ahlijanian M, Flood D, Leven-thal L, Shapiro G, Patzke H, Chesworth R, Koenig G (2012)Modulation of gamma-secretase by EVP-0015962 reducesamyloid deposition and behavioral deficits in Tg2576 mice.Mol Neurodegener 7, 61.

[345] Mitani Y, Akashiba H, Saita K, Yarimizu J, Uchino H, OkabeM, Asai M, Yamasaki S, Nozawa T, Ishikawa N, Shitaka Y,


Ni K, Matsuoka N (2014) Pharmacological characteriza-tion of the novel gamma-secretase modulator AS2715348,a potential therapy for Alzheimer’s disease, in rodents andnonhuman primates. Neuropharmacology 79, 412-419.

[346] Kobayashi T, Iwama S, Fusano A, Kato Y, Ikeda A, TeranishiY, Nishihara A, Tobe M (2014) Design and synthesis ofan aminopiperidine series of gamma-secretase modulators.Bioorg Med Chem Lett 24, 378-381.

[347] Thomas GD, Ye J, De NC, Monopoli A, Ongini E, VictorRG (2012) Treatment with a nitric oxide-donating NSAIDalleviates functional muscle ischemia in the mouse modelof Duchenne muscular dystrophy. PLoS One 7, e49350.

[348] Wagner SL, Zhang C, Cheng S, Nguyen P, Zhang X, Ryn-earson KD, Wang R, Li Y, Sisodia SS, Mobley WC, TanziRE (2014) Soluble gamma-secretase modulators selectivelyinhibit the production of the 42-amino acid amyloid betapeptide variant and augment the production of multiplecarboxy-truncated amyloid beta species. Biochemistry 53,702-713.

[349] Chen JJ, Qian W, Biswas K, Yuan C, Amegadzie A, Liu Q,Nixey T, Zhu J, Ncube M, Rzasa RM, Chavez F Jr, ChenN, Demorin F, Rumfelt S, Tegley CM, Allen JR, Hitch-cock S, Hungate R, Bartberger MD, Zalameda L, Liu Y,McCarter JD, Zhang J, Zhu L, Babu-Khan S, Luo Y, BradleyJ, Wen PH, Reid DL, Koegler F, Dean C Jr, Hickman D,Correll TL, Williamson T, Wood S (2013) Discovery of2-methylpyridine-based biaryl amides as gamma-secretasemodulators for the treatment of Alzheimer’s disease. BioorgMed Chem Lett 23, 6447-6454.

[350] Tian G, Sobotka-Briner CD, Zysk J, Liu X, Birr C, SylvesterMA, Edwards PD, Scott CD, Greenberg BD (2002)Linear non-competitive inhibition of solubilized humangamma-secretase by pepstatin A methylester, L685458,sulfonamides, and benzodiazepines. J Biol Chem 277,31499-31505.

[351] Tian G, Ghanekar SV, Aharony D, Shenvi AB, Jacobs RT,Liu X, Greenberg BD (2003) The mechanism of gamma-secretase: Multiple inhibitor binding sites for transition stateanalogs and small molecule inhibitors. J Biol Chem 278,28968-28975.

[352] Borgegard T, Jureus A, Olsson F, Rosqvist S, SabirshA, Rotticci D, Paulsen K, Klintenberg R, Yan H, Wald-man M, Stromberg K, Nord J, Johansson J, Regner A,Parpal S, Malinowsky D, Radesater AC, Li T, Singh R,Eriksson H, Lundkvist J (2012) First and second gen-eration gamma-secretase modulators (GSMs) modulateamyloid-beta (Abeta) peptide production through differentmechanisms. J Biol Chem 287, 11810-11819.

[353] Sehgelmeble F, Janson J, Ray C, Rosqvist S, GustavssonS, Nilsson LI, Minidis A, Holenz J, Rotticci D, LundkvistJ, Arvidsson PI (2012) Sulfonimidamides as sulfonamidesbioisosteres: Rational evaluation through synthetic, in vitro,and in vivo studies with gamma-secretase inhibitors. ChemMed Chem 7, 396-399.

[354] Wanngren J, Ottervald J, Parpal S, Portelius E, StrombergK, Borgegard T, Klintenberg R, Jureus A, BlomqvistJ, Blennow K, Zetterberg H, Lundkvist J, Rosqvist S,Karlstrom H (2012) Second generation gamma-secretasemodulators exhibit different modulation of Notch beta andAbeta production. J Biol Chem 287, 32640-32650.

[355] Hubbs JL, Fuller NO, Austin WF, Shen R, Creaser SP,McKee TD, Loureiro RM, Tate B, Xia W, Ives J, BronkBS (2012) Optimization of a natural product-based class ofgamma-secretase modulators. J Med Chem 55, 9270-9282.

[356] Tate B, McKee TD, Loureiro RM, Dumin JA, Xia W, PojasekK, Austin WF, Fuller NO, Hubbs JL, Shen R, Jonker J, IvesJ, Bronk BS (2012) Modulation of gamma-secretase for thetreatment of Alzheimer’s disease. Int J Alzheimers Dis 2012,210756.

[357] Loureiro RM, Dumin JA, McKee TD, Austin WF, FullerNO, Hubbs JL, Shen R, Jonker J, Ives J, Bronk BS, TateB (2013) Efficacy of SPI-1865, a novel gamma-secretasemodulator, in multiple rodent models. Alzheimers Res Ther5, 19.

[358] Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendonDC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, GoldeTE (2003) NSAIDs and enantiomers of flurbiprofen targetgamma-secretase and lower Abeta 42 in vivo. J Clin Invest112, 440-449.

[359] Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, FauqA, Golde TE, Koo EH (2003) Evidence that nonsteroidalanti-inflammatory drugs decrease amyloid beta 42 produc-tion by direct modulation of gamma-secretase activity. J BiolChem 278, 31831-31837.

[360] Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF, DondioG, Fontanella L, Misiano P, Bigogno C, Rizzi A, RiccardiB, Biscaioli M, Marchetti S, Puccini P, Catinella S, RondelliI, Cenacchi V, Bolzoni PT, Caruso P, Villetti G, FacchinettiF, Del GE, Moretto N, Imbimbo BP (2005) Synthesis andbiological activity of flurbiprofen analogues as selectiveinhibitors of beta-amyloid(1)(-)(42) secretion. J Med Chem48, 5705-5720.

[361] Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP,Koo EH, Golde TE, Nicolle MM (2007) Chronic adminis-tration of R-flurbiprofen attenuates learning impairments intransgenic amyloid precursor protein mice. BMC Neurosci8, 54.

[362] Zhao X, Rebeck GW, Hoe HS, Andrews PM (2008) Taren-flurbil protection from cytotoxicity is associated with anupregulation of neurotrophins. J Alzheimers Dis 15, 397-407.

[363] Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA,Laughlin MA (2008) Efficacy and safety of tarenflurbil inmild to moderate Alzheimer’s disease: A randomised phaseII trial. Lancet Neurol 7, 483-493.

[364] Green RC, Schneider LS, Amato DA, Beelen AP, WilcockG, Swabb EA, Zavitz KH (2009) Effect of tarenflurbil oncognitive decline and activities of daily living in patientswith mild Alzheimer disease: A randomized controlled trial.JAMA 302, 2557-2564.

[365] Imbimbo BP (2009) Why did tarenflurbil fail in Alzheimer’sdisease? J Alzheimers Dis 17, 757-760.

[366] Sano M (2010) Tarenflurbil: Mechanisms and myths. ArchNeurol 67, 750-752.

[367] Vellas B (2010) Tarenflurbil for Alzheimer’s disease:A “shot on goal” that missed. Lancet Neurol 9,235-237.

[368] Hussain I, Fabregue J, Anderes L, Ousson S, Borlat F, EligertV, Berger S, Dimitrov M, Alattia JR, Fraering PC, BeherD (2013) The role of gamma-secretase activating protein(GSAP) and imatinib in the regulation of gamma-secretaseactivity and amyloid-beta generation. J Biol Chem 288,2521-2531.

[369] Chu J, Lauretti E, Craige CP, Pratico D (2014) Pharmaco-logical modulation of GSAP reduces amyloid-beta levelsand tau phosphorylation in a mouse model of Alzheimer’sdisease with plaques and tangles. J Alzheimers Dis, doi:10.3233/JAD-140105


[370] Coowar D, Couche E, Koncina E (2009) Chromenonederivatives useful for the treatment of neurodegenerative dis-eases. WO-2009130253, Oct-29-2009-Prior. Apr-24-2008.

[371] Tsirulnikov K, Abuladze N, Bragin A, Faull K, Cascio D,Damoiseaux R, Schibler MJ, Pushkin A (2012) Inhibitionof aminoacylase 3 protects rat brain cortex neuronal cellsfrom the toxicity of 4-hydroxy-2-nonenal mercapturate and4-hydroxy-2-nonenal. Toxicol Appl Pharmacol 263, 303-314.

[372] Borger E, Aitken L, Du H, Zhang W, Gunn-Moore FJ, YanSS (2013) Is amyloid binding alcohol dehydrogenase a drugtarget for treating Alzheimer’s disease? Curr Alzheimer Res10, 21-29.

[373] Valasani KR, Hu G, Chaney MO, Yan SS (2013) Structure-based design and synthesis of benzothiazole phosphonateanalogues with inhibitors of human ABAD-Abeta for treat-ment of Alzheimer’s disease. Chem Biol Drug Des 81,238-249.

[374] Vangavaragu JR Valasani KR, Fang D, Williams TD,Yan SS (2014) Determination of small molecule ABADinhibitors crossing blood-brain barrier and pharmacokinet-ics. J Alzheimers Dis, doi: 10.3233/JAD-140252

[375] Sudilovsky A, Turnbull B, Croog SH, Crook T (1987)Angiotensin converting enzyme and memory: Preclinicaland clinical data. Int J Neurol 21-22, 145-162.

[376] Sudilovsky A, Croog S, Crook T, Turnbull B, Testa M,Levine S, Klerman GL (1989) Differential effects ofantihypertensive medications on cognitive functioning. Psy-chopharmacol Bull 25, 133-138.

[377] Domeney AM (1994) Angiotensin converting enzymeinhibitors as potential cognitive enhancing agents. J Psy-chiatry Neurosci 19, 46-50.

[378] Barnes JM, Barnes NM, Costall B, Coughlan J, Kelly ME,Naylor RJ, Tomkins DM, Williams TJ (1992) Angiotensin-converting enzyme inhibition, angiotensin, and cognition. JCardiovasc Pharmacol 19(Suppl 6), S63-S71.

[379] Soto ME, van Kan GA, Nourhashemi F, Gillette-GuyonnetS, Cesari M, Cantet C, Rolland Y, Vellas B (2013)Angiotensin-converting enzyme inhibitors and Alzheimer’sdisease progression in older adults: Results from the Reseausur la Maladie d’Alzheimer Francais cohort. J Am GeriatrSoc 61, 1482-1488.

[380] Gao Y, O’Caoimh R, Healy L, Kerins DM, Eustace J, GuyattG, Sammon D, Molloy DW (2013) Effects of centrally actingACE inhibitors on the rate of cognitive decline in dementia.BMJ Open 3, pii: e002881.

[381] O’Caoimh R, Healy L, Gao Y, Svendrovski A, KerinsDM, Eustace J, Kehoe PG, Guyatt G, Molloy DW (2014)Effects of centrally acting Angiotensin converting enzymeinhibitors on functional decline in patients with Alzheimer’sdisease. J Alzheimers Dis 40, 595-603.

[382] Rozzini L, Chilovi BV, Bertoletti E, Conti M, Del R, Trabuc-chi I, Padovani M, A (2006) Angiotensin converting enzyme(ACE) inhibitors modulate the rate of progression of amnes-tic mild cognitive impairment. Int J Geriatr Psychiatry 21,550-555.

[383] Bernstein KE, Koronyo Y, Salumbides BC, Sheyn J,Pelissier L, Lopes DH, Shah KH, Bernstein EA, Fuchs DT,Yu JJ, Pham M, Black KL, Shen XZ, Fuchs S, Koronyo-Hamaoui M (2014) Angiotensin-converting enzyme over-expression in myelomonocytes prevents Alzheimer’s-likecognitive decline. J Clin Invest 124, 1000-1012.

[384] Wyss JM, Kadish I, van Groen T (2003) Age-related declinein spatial learning and memory: Attenuation by captopril.Clin Exp Hypertens 25, 455-474.

[385] Raghavendra V, Chopra K, Kulkarni SK (2001) Comparativestudies on the memory-enhancing actions of captopril andlosartan in mice using inhibitory shock avoidance paradigm.Neuropeptides 35, 65-69.

[386] Mondadori C, Etienne P (1990) Nootropic effects of ACEinhibitors in mice. Psychopharmacology (Berl) 100, 301-307.

[387] Costall B, Coughlan J, Horovitz ZP, Kelly ME, Naylor RJ,Tomkins DM (1989) The effects of ACE inhibitors capto-pril and SQ29,852 in rodent tests of cognition. PharmacolBiochem Behav 33, 573-579.

[388] Braszko JJ, Karwowska-Polecka W, Halicka D, Gard PR(2003) Captopril and enalapril improve cognition anddepressed mood in hypertensive patients. J Basic Clin Phys-iol Pharmacol 14, 323-343.

[389] Yang WN, Han H, Hu XD, Feng GF, Qian YH (2013)The effects of perindopril on cognitive impairment inducedby d-galactose and aluminum trichloride via inhibition ofacetylcholinesterase activity and oxidative stress. Pharma-col Biochem Behav 114-115, 31-36.

[390] Awasthi H, Kaushal D, Siddiqui HH (2012) Chronic inhibi-tion of central Angiotensin-converting enzyme amelioratescolchicine-induced memory impairment in mice. Sci Pharm80, 647-662.

[391] Tota S, Nath C, Najmi AK, Shukla R, Hanif K (2012) Inhi-bition of central angiotensin converting enzyme amelioratesscopolamine induced memory impairment in mice: Roleof cholinergic neurotransmission, cerebral blood flow andbrain energy metabolism. Behav Brain Res 232, 66-76.

[392] Yamada K, Uchida S, Takahashi S, Takayama M, Nagata Y,Suzuki N, Shirakura S, Kanda T (2010) Effect of a centrallyactive angiotensin-converting enzyme inhibitor, perindopril,on cognitive performance in a mouse model of Alzheimer’sdisease. Brain Res 1352, 176-186.

[393] El Sayed NS, Kassem LA, Heikal OA (2009) Promisingtherapy for Alzheimer’s disease targeting angiotensincon-verting enzyme and the cyclooxygense-2 isoform. DrugDiscov Ther 3, 307-315.

[394] Hou DR, Wang Y, Zhou L, Chen K, Tian Y, Song Z, BaoJ, Yang QD (2008) Altered angiotensin-converting enzymeand its effects on the brain in a rat model of Alzheimerdisease. Chin Med J (Engl) 121, 2320-2323.

[395] Jenkins TA, Chai SY (2007) Effect of chronic angiotensinconverting enzyme inhibition on spatial memory andanxiety-like behaviours in rats. Neurobiol Learn Mem 87,218-224.

[396] Tota S, Kamat PK, Saxena G, Hanif K, Najmi AK, NathC (2012) Central angiotensin converting enzyme facilitatesmemory impairment in intracerebroventricular streptozo-tocin treated rats. Behav Brain Res 226, 317-330.

[397] Louis WJ, Mander AG, Dawson M, O’Callaghan C, ConwayEL (1999) Use of computerized neuropsychological tests(CANTAB) to assess cognitive effects of antihypertensivedrugs in the elderly. Cambridge Neuropsychological TestAutomated Battery. J Hypertens 17, 1813-1819.

[398] Braszko JJ, Paslawski L, Karwowska-Polecka W, HolowniaA (2000) Trandolapril attenuates acquisition of conditionedavoidance in rats. Pol J Pharmacol 52, 195-201.

[399] Nikolova JG, Getova DP, Nikolov FP (2000) Effects of ACE-inhibitors on learning and memory processes in rats. FoliaMed (Plovdiv) 42, 47-51.

[400] MacLullich AM, Ferguson KJ, Reid LM, Deary IJ, StarrJM, Wardlaw JM, Walker BR, Andrew R, Seckl JR (2012)11beta-hydroxysteroid dehydrogenase type 1, brain atrophyand cognitive decline. Neurobiol Aging 33, 207-208.


[401] Marek GJ, Katz DA, Meier A, Greco N, Zhang W, Liu W,Lenz RA (2014) Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer’s disease. AlzheimersDement, doi: 10.1016/j.jalz.2013.09.010

[402] Diepenbroek M, Casadei N, Esmer H, Saido TC, Takano J,Kahle PJ, Nixon RA, Rao MV, Melki R, Pieri L, Helling S,Marcus K, Krueger R, Masliah E, Riess O, Nuber S (2014)Overexpression of the calpain-specific inhibitor calpastatinreduces human alpha-synuclein processing, aggregation andsynaptic impairment in [A30P]alphaSyn transgenic mice.Hum Mol Genet, doi: 10.1093/hmg/ddu112

[403] Neuhof C, Fabiunke V, Deibele K, Speth M, Moller A,Lubisch W, Fritz H, Tillmanns H, Neuhof H (2004) Reduc-tion of myocardial infarction by calpain inhibitors A-705239and A-705253 in isolated perfused rabbit hearts. Biol Chem385, 1077-1082.

[404] Neuhof C, Fabiunk V, Speth M, Moller A, Fritz F, Till-manns H, Neuhof H, Erdogan A (2008) Reduction ofmyocardial infarction by postischemic administration of thecalpain inhibitor A-705253 in comparison to the Na(+)/H(+)exchange inhibitor Cariporide in isolated perfused rabbithearts. Biol Chem 389, 1505-1512.

[405] Nangle MR, Cotter MA, Cameron NE (2006) The calpaininhibitor, A-705253, corrects penile nitrergic nerve dysfunc-tion in diabetic mice. Eur J Pharmacol 538, 148-153.

[406] Nimmrich V, Szabo R, Nyakas C, Granic I, Reymann KG,Schroder UH, Gross G, Schoemaker H, Wicke K, Moller A,Luiten P (2008) Inhibition of calpain prevents N-Methyl-D-aspartate-induced degeneration of the nucleus basalis andassociated behavioral dysfunction. J Pharmacol Exp Ther327, 343-352.

[407] Nimmrich V, Reymann KG, Strassburger M, Schoder UH,Gross G, Hahn A, Schoemaker H, Wicke K, Moller A (2010)Inhibition of calpain prevents NMDA-induced cell death andbeta-amyloid-induced synaptic dysfunction in hippocampalslice cultures. Br J Pharmacol 159, 1523-1531.

[408] Sinjoanu RC, Kleinschmidt S, Bitner RS, Brioni JD, MoellerA, Ferreira A (2008) The novel calpain inhibitor A-705253potently inhibits oligomeric beta-amyloid-induced dynamin1 and tau cleavage in hippocampal neurons. Neurochem Int53, 79-88.

[409] Granic I, Nyakas C, Luiten PG, Eisel UL, Halmy LG,Gross G, Schoemaker H, Moller A, Nimmrich V (2010)Calpain inhibition prevents amyloid-beta-induced neurode-generation and associated behavioral dysfunction in rats.Neuropharmacology 59, 334-342.

[410] Nikkel AL, Martino B, Markosyan S, Brederson JD,Medeiros R, Moeller A, Bitner RS (2012) The novel calpaininhibitor A-705253 prevents stress-induced tau hyperphos-phorylation in vitro and in vivo. Neuropharmacology 63,606-612.

[411] Medeiros R, Kitazawa M, Chabrier MA, Cheng D,Baglietto-Vargas D, Kling A, Moeller A, Green KN,Laferla FM (2012) Calpain inhibitor A-705253 mitigatesAlzheimer’s disease-like pathology and cognitive decline inaged 3xTgAD mice. Am J Pathol 181, 616-625.

[412] Saatman KE, Murai H, Bartus RT, Smith DH, Hayward NJ,Perri BR, McIntosh TK (1996) Calpain inhibitor AK295attenuates motor and cognitive deficits following experi-mental brain injury in the rat. Proc Natl Acad Sci U S A93, 3428-3433.

[413] Lee E, Eom JE, Kim HL, Baek KH, Jun KY, Kim HJ, Lee M,Mook-Jung I, Kwon Y (2013) Effect of conjugated linoleicacid, mu-calpain inhibitor, on pathogenesis of Alzheimer’sdisease. Biochim Biophys Acta 1831, 709-718.

[414] Sun MK, Alkon DL (2002) Carbonic anhydrase gating ofattention: Memory therapy and enhancement. Trends Phar-macol Sci 23, 83-89.

[415] Draghici B, Vullo D, Akocak S, Walker EA, Supuran CT,Ilies MA (2014) Ethylene bis-imidazoles are highly potentand selective activators for isozymes VA and VII of carbonicanhydrase, with a potential nootropic effect. Chem Commun(Camb) 50, 5980-5983.

[416] Jaudzems K, Kuka J, Gutsaits A, Zinovjevs K, KalvinshI, Liepinsh E, Liepinsh E, Dambrova M (2009) Inhibitionof carnitine acetyltransferase by mildronate, a regulator ofenergy metabolism. J Enzyme Inhib Med Chem 24, 1269-1275.

[417] Beitnere U, van GT, Kumar A, Jansone B, Klusa V, Kadish I(2014) Mildronate improves cognition and reduces amyloid-beta pathology in transgenic Alzheimer’s disease mice. JNeurosci Res 92, 338-346.

[418] Klusa V, Muceniece R, Isajevs S, Isajeva D, Beitnere U,Mandrika I, Pupure J, Rumaks J, Jansone B, Kalvinsh I,Vinters HV (2013) Mildronate enhances learning/memoryand changes hippocampal protein expression in trained rats.Pharmacol Biochem Behav 106, 68-76.

[419] Klusa V, Beitnere U, Pupure J, Isajevs S, Rumaks J,Svirskis S, Dzirkale Z, Kalvinsh I (2013) Mildronate andits neuroregulatory mechanisms: Targeting the mitochon-dria, neuroinflammation, and protein expression. Medicina(Kaunas) 49, 301-309.

[420] Ramcharitar J, Albrecht S, Afonso VM, Kaushal V, BennettDA, Leblanc AC (2013) Cerebrospinal fluid tau cleaved bycaspase-6 reflects brain levels and cognition in aging andAlzheimer disease. J Neuropathol Exp Neurol 72, 824-832.

[421] Ramcharitar J, Afonso VM, Albrecht S, Bennett DA,Leblanc AC (2013) Caspase-6 activity predicts lowerepisodic memory ability in aged individuals. NeurobiolAging 34, 1815-1824.

[422] Di Giovanni S, Eleuteri S, Paleologou KE, Yin G, Zweck-stetter M, Carrupt PA, Lashuel HA (2010) Entacaponeand tolcapone, two catechol O-methyltransferase inhibitors,block fibril formation of alpha-synuclein and beta-amyloidand protect against amyloid-induced toxicity. J Biol Chem285, 14941-14954.

[423] Mohamed T, Hoang T, Jelokhani-Niaraki M, Rao PP (2013)Tau-derived-hexapeptide (306)VQIVYK(311) aggregationinhibitors: Nitrocatechol moiety as a pharmacophore in drugdesign. ACS Chem Neurosci 4, 1559-1570.

[424] Hook G, Hook V, Kindy M (2011) The cysteine proteaseinhibitor, E64d, reduces brain amyloid-beta and improvesmemory deficits in Alzheimer’s disease animal models byinhibiting cathepsin B, but not BACE1, beta-secretase activ-ity. J Alzheimers Dis 26, 387-408.

[425] Hook G, Yu J, Toneff T, Kindy M, Hook V (2014) Brainpyroglutamate amyloid-beta is produced by cathepsin B andis reduced by the cysteine protease inhibitor E64d, represent-ing a potential Alzheimer’s disease therapeutic. J AlzheimersDis 41, 129-149.

[426] Di Scala C, Yahi N, Lelievre C, Garmy N, ChahinianH, Fantini J (2013) Biochemical identification of a linearcholesterol-binding domain within Alzheimer’s beta amy-loid peptide. ACS Chem Neurosci 4, 509-517.

[427] Lee HJ, Korshavn KJ, Kochi A, Derrick JS, Lim MH (2014)Cholesterol and metal ions in Alzheimer’s disease. ChemSoc Rev, doi: 10.1039/C4CS00005F

[428] Wood WG, Li L, Muller WE, Eckert GP (2014) Cholesterolas a causative factor in Alzheimer’s disease: A debatablehypothesis. J Neurochem 129, 559-572.


[429] Hudry E, Van DD, Kulik W, De Deyn PP, Stet FS, Ahouan-sou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P,Cartier N (2010) Adeno-associated virus gene therapy withcholesterol 24-hydroxylase reduces the amyloid pathologybefore or after the onset of amyloid plaques in mouse modelsof Alzheimer’s disease. Mol Ther 18, 44-53.

[430] Choi SH, Aid S, Caracciolo L, Sakura MS, Niikura T,Matsuoka Y, Turner RS, Mattson MP, Bosetti F (2013)Cyclooxygenase-1 inhibition reduces amyloid pathologyand improves memory deficits in a mouse model ofAlzheimer’s disease. J Neurochem 124, 59-68.

[431] Subaiea GM, Adwan LI, Ahmed AH, Stevens KE, Zawia NH(2013) Short-term treatment with tolfenamic acid improvescognitive functions in Alzheimer’s disease mice. NeurobiolAging 34, 2421-2430.

[432] Adwan L, Subaiea GM, Zawia NH (2014) Tolfenamic aciddownregulates BACE1 and protects against lead-inducedupregulation of Alzheimer’s disease related biomarkers.Neuropharmacology 79, 596-602.

[433] Shi S, Wang Z, Qiao Z (2013) The multifunctional anti-inflammatory drugs used in the therapy of Alzheimer’sdisease. Curr Med Chem 20, 2583-2588.

[434] Lin CH, Chen PK, Chang YC, Chuo LJ, Chen YS, TsaiGE, Lane HY (2014) Benzoate, a d-amino Acid oxidaseinhibitor, for the treatment of early-phase Alzheimer dis-ease: A randomized, double-blind, placebo-controlled trial.Biol Psychiatry 75, 678-685.

[435] Hondo T, Warizaya M, Niimi T, Namatame I, Yam-aguchi T, Nakanishi K, Hamajima T, Harada K, SakashitaH, Matsumoto Y, Orita M, Takeuchi M (2013) 4-Hydroxypyridazin-3(2H)-one derivatives as novel D-aminoacid oxidase inhibitors. J Med Chem 56, 3582-3592.

[436] Kosaraju J, Gali CC, Khatwal RB, Dubala A, Chinni S,Holsinger RM, Madhunapantula VS, Muthureddy NatarajSK, Basavan D (2013) Saxagliptin: A dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer’sdisease. Neuropharmacology 72, 291-300.

[437] Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S,Muthureddy Nataraj SK, Basavan D (2013) Vildagliptin:An anti-diabetes agent ameliorates cognitive deficits andpathology observed in streptozotocin-induced Alzheimer’sdisease. J Pharm Pharmacol 65, 1773-1784.

[438] Frost JL, Le KX, Cynis H, Ekpo E, Kleinschmidt M, Pal-mour RM, Ervin FR, Snigdha S, Cotman CW, Saido TC,Vassar RJ, George-Hyslop PS, Ikezu T, Schilling S, DemuthHU, Lemere CA (2013) Pyroglutamate-3 amyloid-betadeposition in the brains of humans, non-human primates,canines, and Alzheimer disease-like transgenic mouse mod-els. Am J Pathol 183, 369-381.

[439] Sun N, Hartmann R, Lecher J, Stoldt M, Funke SA, GremerL, Ludwig HH, Demuth HU, Kleinschmidt M, Willbold D(2012) Structural analysis of the pyroglutamate-modifiedisoform of the Alzheimer’s disease-related amyloid-betausing NMR spectroscopy. J Pept Sci 18, 691-695.

[440] Valenti MT, Bolognin S, Zanatta C, Donatelli L, InnamoratiG, Pampanin M, Zanusso G, Zatta P, Dalle CL (2013)Increased glutaminyl cyclase expression in peripheral bloodof Alzheimer’s disease patients. J Alzheimers Dis 34, 263-271.

[441] Morawski M, Schilling S, Kreuzberger M, Waniek A,Jager C, Koch B, Cynis H, Kehlen A, Arendt T, Hartlage-Rubsamen M, Demuth HU, Rossner S (2014) Glutaminylcyclase in human cortex: Correlation with (pGlu)-amyloid-beta load and cognitive decline in Alzheimer’s disease. JAlzheimers Dis 39, 385-400.

[442] Ramsbeck D, Buchholz M, Koch B, Bohme L, HoffmannT, Demuth HU, Heiser U (2013) Structure-activity relation-ships of benzimidazole-based glutaminyl cyclase inhibitorsfeaturing a heteroaryl scaffold. J Med Chem 56, 6613-6625.

[443] Ma T (2014) GSK3 in Alzheimer’s disease: Mind the iso-forms. J Alzheimers Dis 39, 707-710.

[444] Avila J, Leon-Espinosa G, Garcia E, Garcia-Escudero V,Hernandez F, Defelipe J (2012) Tau phosphorylation byGSK3 in different conditions. Int J Alzheimers Dis 2012,578373.

[445] Hernandez F, Lucas JJ, Avila J (2013) GSK3 and tau: Twoconvergence points in Alzheimer’s disease. J Alzheimers Dis33, S141-S144.

[446] Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ (2012)AGEs induce Alzheimer-like tau pathology and memorydeficit via RAGE-mediated GSK-3 activation. NeurobiolAging 33, 1400-1410.

[447] Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG, CotteA, Jaworski T, Tobon-Velasco JC, Devijver H, Garcia-Mayoral MF, Van Leuven F, Hayes JD, Bertho G, CuadradoA (2012) Structural and functional characterization of Nrf2degradation by the glycogen synthase kinase 3/beta-TrCPaxis. Mol Cell Biol 32, 3486-3499.

[448] Rocha-Souto B, Coma M, Perez-Nievas BG, Scotton TC,Siao M, Sanchez-Ferrer P, Hashimoto T, Fan Z, Hudry E,Barroeta I, Sereno L, Rodriguez M, Sanchez MB, HymanBT, Gomez-Isla T (2012) Activation of glycogen synthasekinase-3 beta mediates beta-amyloid induced neuritic dam-age in Alzheimer’s disease. Neurobiol Dis 45, 425-437.

[449] Cai Z, Zhao Y, Zhao B (2012) Roles of glycogen synthasekinase 3 in Alzheimer’s disease. Curr Alzheimer Res 9, 864-879.

[450] Mondragon-Rodriguez S, Perry G, Zhu X, Moreira PI,Williams S (2012) Glycogen synthase kinase 3: A point ofintegration in Alzheimer’s disease and a therapeutic target?Int J Alzheimers Dis 2012, 276803.

[451] Parr C, Carzaniga R, Gentleman SM, Van Leuven F, WalterJ, Sastre M (2012) Glycogen synthase kinase 3 inhibitionpromotes lysosomal biogenesis and autophagic degradationof the amyloid-beta precursor protein. Mol Cell Biol 32,4410-4418.

[452] Maurin H, Lechat B, Dewachter I, Ris L, Louis JV,Borghgraef P, Devijver H, Jaworski T, Van Leuven F(2013) Neurological characterization of mice deficient inGSK3alpha highlight pleiotropic physiological functions incognition and pathological activity as tau kinase. Mol Brain6, 27.

[453] King MK, Pardo M, Cheng Y, Downey K, Jope RS, BeurelE (2014) Glycogen synthase kinase-3 inhibitors: Rescuersof cognitive impairments. Pharmacol Ther 141, 1-12.

[454] Medina M, Avila J (2014) New insights into the role ofglycogen synthase kinase-3 in Alzheimer’s disease. ExpertOpin Ther Targets 18, 69-77.

[455] Cociorva OM, Li B, Nomanbhoy T, Li Q, Nakamura A,Nakamura K, Nomura M, Okada K, Seto S, Yumoto K,Liyanage M, Zhang MC, Aban A, Leen B, SzardeningsAK, Rosenblum JS, Kozarich JW, Kohno Y, Shreder KR(2011) Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogensynthase kinase-3beta. Bioorg Med Chem Lett 21, 5948-5951.

[456] Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, Sun X, ZhaoL, Yu M, Xu Z, Dong W, Qin Y, Fei G, Zhong C, Xu TL(2010) Powerful beneficial effects of benfotiamine on cog-nitive impairment and beta-amyloid deposition in amyloid


precursor protein/presenilin-1 transgenic mice. Brain 133,1342-1351.

[457] Sun XJ, Zhao L, Zhao N, Pan XL, Fei GQ, Jin LR, ZhongCJ (2012) Benfotiamine prevents increased beta-amyloidproduction in HEK cells induced by high glucose. NeurosciBull 28, 561-566.

[458] Wang S, Meades C, Wood G, Duncan K Zhevela D, Fis-cher P (2004) Therapeutic applications of 2-substituted4-heteroarylpyrimidines. WO-2004056368, Jul-08-2004-Prior. Dec-19-2002.

[459] Fukunaga K, Uehara F, Aritomo K, Shoda A, Hiki S,Okuyama M, Usui Y, Watanabe K, Yamakoshi K, Kohara T,Hanano T, Tanaka H, Tsuchiya S, Sunada S, Saito K, EguchiJ, Yuki S, Asano S, Tanaka S, Mori A, Yamagami K, BabaH, Horikawa T, Fujimura M (2013) 2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; A new class of potent, selectiveand orally active glycogen synthase kinase-3beta inhibitors.Bioorg Med Chem Lett 23, 6933-6937.

[460] Uehara F, Shoda A, Aritomo K, Fukunaga K, Watanabe K,Ando R, Shinoda M, Ueno H, Kubodera H, Sunada S, SaitoK, Kaji T, Asano S, Eguchi J, Yuki S, Tanaka S, Yoneyama Y,Niwa T (2013) 6-(4-Pyridyl)pyrimidin-4(3H)-ones as CNSpenetrant glycogen synthase kinase-3beta inhibitors. BioorgMed Chem Lett 23, 6928-6932.

[461] Kurumbail R, Andrle S, Asbill J, Boyd J, Cadelina G, ChangG, Chang J, Che Y, Conn E, Cook J, Cosgrove P, DePasqualeM, Durham R, Enerson B, Lefker B, Nguyen H, Lanyon L,Lopresti-Morrow L, Noe M, Nolan C, Para K, Perez J, Pine J,Plummer M, Richter K, Sarver R, Schachter J, Sundaram S,Shanmugasundaram V, Taylor C, Trapa P, Wang H, WithkaJ, Zagouras P, Zhou R, Liquia (2012) Oxazole GSK-3betainhibitors for Alzheimer’s disease: From HTS hit to effica-cious lead. 244th ACS National Meeting & Exposition, Aug.21-MEDI-222.

[462] Wang W, Yang Y, Ying C, Li W, Ruan H, Zhu X, You Y,Han Y, Chen R, Wang Y, Li M (2007) Inhibition of glycogensynthase kinase-3beta protects dopaminergic neurons fromMPTP toxicity. Neuropharmacology 52, 1678-1684.

[463] Williams M (2009) Progress in Alzheimer’s disease drugdiscovery: An update. Curr Opin Investig Drugs 10, 23-34.

[464] Saitoh M, Kunitomo J, Kimura E, Hayase Y, Kobayashi H,Uchiyama N, Kawamoto T, Tanaka T, Mol CD, Dougan DR,Textor GS, Snell GP, Itoh F (2009) Design, synthesis andstructure-activity relationships of 1,3,4-oxadiazole deriva-tives as novel inhibitors of glycogen synthase kinase-3beta.Bioorg Med Chem 17, 2017-2029.

[465] Saitoh M, Kunitomo J, Kimura E, Iwashita H, Uno Y, OnishiT, Uchiyama N, Kawamoto T, Tanaka T, Mol CD, DouganDR, Textor GP, Snell GP, Takizawa M, Itoh F, Kori M(2009) 2-3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl-5-methyl-1,3,4-oxadiazol e derivatives as novel inhibitors ofglycogen synthase kinase-3beta with good brain permeabil-ity. J Med Chem 52, 6270-6286.

[466] Saitoh M, Kunitomo J, Kimura E, Yamano T, Itoh F, Kori M(2010) Enantioselective synthesis of the novel chiral sulfox-ide derivative as a glycogen synthase kinase 3beta inhibitor.Chem Pharm Bull (Tokyo) 58, 1252-1254.

[467] Onishi T, Iwashita H, Uno Y, Kunitomo J, SaitohM, Kimura E, Fujita H, Uchiyama N, Kori M,Takizawa M (2011) A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-4-[(S)-methylsulfinyl]phenyl-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phospho-rylation and ameliorates cognitive deficits in a transgenicmodel of Alzheimer’s disease. J Neurochem 119, 1330-1340.

[468] Ding S, Wu TY, Brinker A, Peters EC, Hur W, Gray NS,Schultz PG (2003) Synthetic small molecules that controlstem cell fate. Proc Natl Acad Sci U S A 100, 7632-7637.

[469] Paterniti I, Mazzon E, Gil C, Impellizzeri D, Palomo V,Redondo M, Perez DI, Esposito E, Martinez A, Cuzzocrea S(2011) PDE 7 inhibitors: New potential drugs for the therapyof spinal cord injury. PLoS One 6, e15937.

[470] Lipina TV, Palomo V, Gil C, Martinez A, Roder JC(2013) Dual inhibitor of PDE7 and GSK-3-VP1.15 acts asantipsychotic and cognitive enhancer in C57BL/6J mice.Neuropharmacology 64, 205-214.

[471] Lo Monte F, Kramer T, Gu J, Brodrecht M, PilakowskiJ, Fuertes A, Dominguez JM, Plotkin B, Eldar-FinkelmanH, Schmidt B (2013) Structure-based optimization ofoxadiazole-based GSK-3 inhibitors. Eur J Med Chem 61,26-40.

[472] Voigt B, Krug M, Schachtele C, Totzke F, Hilgeroth A (2008)Probing novel 1-aza-9-oxafluorenes as selective GSK-3betainhibitors. Chem Med Chem 3, 120-126.

[473] Tell V, Holzer M, Herrmann L, Mahmoud KA, SchachteleC, Totzke F, Hilgeroth A (2012) Multitargeted drugdevelopment: Discovery and profiling of dihydroxy sub-stituted 1-aza-9-oxafluorenes as lead compounds targetingAlzheimer disease relevant kinases. Bioorg Med Chem Lett22, 6914-6918.

[474] Hilgeroth A, Tell V, Kramer S, Totzke F, Schachtele C (2014)Approaches to a multitargeting drug development: First pro-filed 3- ethoxycarbonyl-1-aza-9-oxafluorenes representinga perspective compound class targeting Alzheimer diseaserelevant kinases CDK1, CDK5 and GSK-3beta. Med Chem10, 90-97.

[475] Ye Q, Li M, Zhou YB, Cao JY, Xu L, Li YJ, Han L, GaoJR, Hu YZ, Li J (2013) Design, synthesis, and evaluation of3-aryl-4-pyrrolyl-maleimides as glycogen synthase kinase-3beta inhibitors. Arch Pharm (Weinheim) 346, 349-358.

[476] Ye Q, Li M, Zhou Y, Pang T, Xu L, Cao J, Han L, Li Y, WangW, Gao J, Li J (2013) Synthesis and biological evaluation of3-benzisoxazolyl-4-indolylmaleimides as potent, selectiveinhibitors of glycogen synthase kinase-3beta. Molecules 18,5498-5516.

[477] Palomo V, Soteras I, Perez DI, Perez C, Gil C, CampilloNE, Martinez A (2011) Exploring the binding sites ofglycogen synthase kinase 3. Identification and characteri-zation of allosteric modulation cavities. J Med Chem 54,8461-8470.

[478] Palomo V, Perez DI, Perez C, Morales-Garcia JA, SoterasI, Alonso-Gil S, Encinas A, Castro A, Campillo NE,Perez-Castillo A, Gil C, Martinez A (2012) 5-imino-1,2,4-thiadiazoles: First small molecules as substrate competitiveinhibitors of glycogen synthase kinase 3. J Med Chem 55,1645-1661.

[479] Perez DI, Palomo V, Perez C, Gil C, Dans PD, Luque FJ,Conde S, Martinez A (2011) Switching reversibility to irre-versibility in glycogen synthase kinase 3 inhibitors: Cluesfor specific design of new compounds. J Med Chem 54,4042-4056.

[480] Perez DI, Pistolozzi M, Palomo V, Redondo M, FortugnoC, Gil C, Felix G, Martinez A, Bertucci C (2012) 5-Imino-1,2-4-thiadiazoles and quinazolines derivatives as glycogensynthase kinase 3beta (GSK-3beta) and phosphodiesterase7 (PDE7) inhibitors: Determination of blood-brain barrierpenetration and binding to human serum albumin. Eur JPharm Sci 45, 677-684.

[481] Noh MY, Chun K, Kang BY, Kim H, Park JS, Lee HC,Kim YH, Ku S, Kim SH (2013) Newly developed glycogen


synthase kinase-3 (GSK-3) inhibitors protect neuronal cellsdeath in amyloid-beta induced cell model and in a transgenicmouse model of Alzheimer’s disease. Biochem Biophys ResCommun 435, 274-281.

[482] Zhou X, Zhou J, Li X, Guo C, Fang T, Chen Z (2011) GSK-3beta inhibitors suppressed neuroinflammation in rat cortexby activating autophagy in ischemic brain injury. BiochemBiophys Res Commun 411, 271-275.

[483] Zhang P, Hu HR, Huang ZH, Lei JY, Chu Y, Ye DY (2012)Identification of novel scaffold of benzothiazepinonesas non-ATP competitive glycogen synthase kinase-3betainhibitors through virtual screening. Bioorg Med Chem Lett22, 7232-7236.

[484] Zhang P, Hu HR, Bian SH, Huang ZH, Chu Y, Ye DY(2013) Design, synthesis and biological evaluation of ben-zothiazepinones (BTZs) as novel non-ATP competitiveinhibitors of glycogen synthase kinase-3beta (GSK-3beta).Eur J Med Chem 61, 95-103.

[485] Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D,Eldar-Finkelman H (2013) Inhibition of glycogen synthasekinase-3 ameliorates beta-amyloid pathology and restoreslysosomal acidification and mammalian target of rapamycinactivity in the Alzheimer disease mouse model: In vivo andin vitro studies. J Biol Chem 288, 1295-1306.

[486] Lo Monte F, Kramer T, Gu J, Anumala UR, Marinelli L,La P, Novellino V, Franco E, Demedts B, Van Leuven D,Fuertes F, Dominguez A, Plotkin JM, Eldar-Finkelman B,Schmidt H, B (2012) Identification of glycogen synthasekinase-3 inhibitors with a selective sting for glycogen syn-thase kinase-3alpha. J Med Chem 55, 4407-4424.

[487] Bhat RV, Budd Haeberlein SL, Avila J (2004) Glycogen syn-thase kinase 3: A drug target for CNS therapies. J Neurochem89, 1313-1317.

[488] Berg S, Bergh M, Hellberg S, Hogdin K, Lo-Alfredsson Y,Soderman P, von BS, Weigelt T, Ormo M, Xue Y, TuckerJ, Neelissen J, Jerning E, Nilsson Y, Bhat R (2012) Discov-ery of novel potent and highly selective glycogen synthasekinase-3beta (GSK3beta) inhibitors for Alzheimer’s dis-ease: Design, synthesis, and characterization of pyrazines.J Med Chem 55, 9107-9119.

[489] Georgievska B, Sandin J, Doherty J, Mortberg A, NeelissenJ, Andersson A, Gruber S, Nilsson Y, Schott P, Arvids-son PI, Hellberg S, Osswald G, Berg S, Falting J, Bhat RV(2013) AZD1080, a novel GSK3 inhibitor, rescues synap-tic plasticity deficits in rodent brain and exhibits peripheraltarget engagement in humans. J Neurochem 125, 446-456.

[490] King MR, Anderson NJ, Guernsey LS, Jolivalt CG (2013)Glycogen synthase kinase-3 inhibition prevents learningdeficits in diabetic mice. J Neurosci Res 91, 506-514.

[491] Coffman K, Brodney M, Cook J, Lanyon L, Pandit J,Sakya S, Schachter J, Tseng-Lovering E, Wessel M (2011)6-amino-4-(pyrimidin-4-yl)pyridones: Novel glycogen syn-thase kinase-3beta inhibitors. Bioorg Med Chem Lett 21,1429-1433.

[492] Castro A, Encinas A, Gil C, Brase S, Porcal W, Perez C,Moreno FJ, Martinez A (2008) Non-ATP competitive glyco-gen synthase kinase 3beta (GSK-3beta) inhibitors: Studyof structural requirements for thiadiazolidinone derivatives.Bioorg Med Chem 16, 495-510.

[493] del Ser T, Steinwachs KC, Gertz HJ, Andres MV, Gomez-Carrillo B, Medina M, Vericat JA, Redondo P, Fleet D, LeonT (2013) Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: A pilot study. J Alzheimers Dis 33,205-215.

[494] Hoglinger GU, Huppertz HJ, Wagenpfeil S, Andres MV,Belloch V, Leon T, del ST (2014) Tideglusib reduces pro-gression of brain atrophy in progressive supranuclear palsyin a randomized trial. Mov Disord 29, 479-487.

[495] Tolosa E, Litvan I, Hoglinger GU, Burn D, Lees A, AndresMV, Gomez-Carrillo B, Leon T, del ST (2014) A phase 2 trialof the GSK-3 inhibitor tideglusib in progressive supranu-clear palsy. Mov Disord 29, 470-478.

[496] Thatcher GR, Bennett BM, Reynolds JN (2005) Nitric oxidemimetic molecules as therapeutic agents in Alzheimer’s dis-ease. Curr Alzheimer Res 2, 171-182.

[497] Graff J, Tsai LH (2013) The potential of HDAC inhibitorsas cognitive enhancers. Annu Rev Pharmacol Toxicol 53,311-330.

[498] Whittle N, Singewald N (2014) HDAC inhibitors as cogni-tive enhancers in fear, anxiety and trauma therapy: Wheredo we stand? Biochem Soc Trans 42, 569-581.

[499] Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A (2013)Loss of HDAC5 impairs memory function: Implications forAlzheimer’s disease. J Alzheimers Dis 33, 35-44.

[500] Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, ZhaoWN, Nieland TJ, Guan JS, Kuhnle CE, Tang W, Barker DD,Mazitschek R, Schreiber SL, Tsai LH, Haggarty SJ (2013)Crebinostat: A novel cognitive enhancer that inhibits histonedeacetylase activity and modulates chromatin-mediatedneuroplasticity. Neuropharmacology 64, 81-96.

[501] Zhang ZY, Schluesener HJ (2013) Oral administrationof histone deacetylase inhibitor MS-275 ameliorates neu-roinflammation and cerebral amyloidosis and improvesbehavior in a mouse model. J Neuropathol Exp Neurol 72,178-185.

[502] Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL,Gottesfeld JM (2006) Histone deacetylase inhibitors reversegene silencing in Friedreich’s ataxia. Nat Chem Biol 2, 551-558.

[503] Rai M, Soragni E, Jenssen K, Burnett R, Herman D, Cop-pola G, Geschwind DH, Gottesfeld JM, Pandolfo M (2008)HDAC inhibitors correct frataxin deficiency in a Friedreichataxia mouse model. PLoS One 3, e1958.

[504] Lu J, Yang C, Chen M, Ye DY, Lonser RR, Brady RO,Zhuang Z (2011) Histone deacetylase inhibitors prevent thedegradation and restore the activity of glucocerebrosidasein Gaucher disease. Proc Natl Acad Sci U S A 108, 21200-21205.

[505] Yu CW, Chang PT, Hsin LW, Chern JW (2013) Quinazolin-4-one derivatives as selective histone deacetylase-6inhibitors for the treatment of Alzheimer’s disease. J MedChem 56, 6775-6791.

[506] Govindarajan N, Agis-Balboa RC, Walter J, SananbenesiF, Fischer A (2011) Sodium butyrate improves memoryfunction in an Alzheimer’s disease mouse model whenadministered at an advanced stage of disease progression.J Alzheimers Dis 26, 187-197.

[507] Govindarajan N, Rao P, Burkhardt S, Sananbenesi F,Schluter OM, Bradke F, Lu J, Fischer A (2013) ReducingHDAC6 ameliorates cognitive deficits in a mouse model forAlzheimer’s disease. EMBO Mol Med 5, 52-63.

[508] Ji M, Dong L, Jia M, Liu W, Zhang M, Ju L, Yang J, XieZ, Yang J (2014) Epigenetic enhancement of brain-derivedneurotrophic factor signaling pathway improves cognitiveimpairments induced by isoflurane exposure in aged rats.Mol Neurobiol, doi: 10.1007/s12035-014-8659-z

[509] Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ,Sweatt JD, Rumbaugh G (2010) Inhibitors of class 1 histonedeacetylases reverse contextual memory deficits in a mouse


model of Alzheimer’s disease. Neuropsychopharmacology35, 870-880.

[510] Venkataramani V, Rossner C, Iffland L, Schweyer S, Tam-boli IY, Walter J, Wirths O, Bayer TA (2010) Histonedeacetylase inhibitor valproic acid inhibits cancer cell pro-liferation via down-regulation of the Alzheimer amyloidprecursor protein. J Biol Chem 285, 10678-10689.

[511] Nuutinen T, Suuronen T, Kauppinen A, Salminen A (2010)Valproic acid stimulates clusterin expression in human astro-cytes: Implications for Alzheimer’s disease. Neurosci Lett475, 64-68.

[512] Yang W, Chauhan A, Mehta S, Mehta P, Gu F, Chauhan V(2014) Trichostatin A increases the levels of plasma gelsolinand amyloid beta-protein in a transgenic mouse model ofAlzheimer’s disease. Life Sci 99, 31-36.

[513] Butler KV, Kalin J, Brochier C, Vistoli G, Langley B,Kozikowski AP (2010) Rational design and simple chem-istry yield a superior, neuroprotective HDAC6 inhibitor,tubastatin A. J Am Chem Soc 132, 10842-10846.

[514] Benner L, Kalin JH, Kozikowski A, Gordon MN, Morgan D,Selenica MB (2012) Selective HDAC6 inhibition decreasestau levels and imrpoves memory deficits in the rtg4510mouse model. Society for Neuroscience, New Orleans,Poster 150.04-Sunday, November 14, 2012.

[515] Noack M, Leyk J, Richter-Landsberg C (2014) HDAC6inhibition results in tau acetylation and modulates tau phos-phorylation and degradation in oligodendrocytes. Glia 62,535-547.

[516] Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A,Frechilla D, Del RJ, Garcia-Osta A (2009) Phenylbutyrateameliorates cognitive deficit and reduces tau pathology inan Alzheimer’s disease mouse model. Neuropsychopharma-cology 34, 1721-1732.

[517] Ricobaraza A, Cuadrado-Tejedor M, Garcia-Osta A (2011)Long-term phenylbutyrate administration prevents memorydeficits in Tg2576 mice by decreasing Abeta. Front Biosci(Elite Ed) 3, 1375-1384.

[518] Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-OtanoI, Garcia-Osta A (2012) Phenylbutyrate rescues dendriticspine loss associated with memory deficits in a mouse modelof Alzheimer disease. Hippocampus 22, 1040-1050.

[519] Cuadrado-Tejedor M, Ricobaraza AL, Torrijo R, FrancoR, Garcia-Osta A (2013) Phenylbutyrate is a multifaceteddrug that exerts neuroprotective effects and reverses theAlzheimer s disease-like phenotype of a commonly usedmouse model. Curr Pharm Des 19, 5076-5084.

[520] Wiley JC, Pettan-Brewer C, Ladiges WC (2011) Phenylbu-tyric acid reduces amyloid plaques and rescues cognitivebehavior in AD transgenic mice. Aging Cell 10, 418-428.

[521] Cuadrado-Tejedor M, Garcia-Osta A, Ricobaraza A, Oyarz-abal J, Franco R (2011) Defining the mechanism of actionof 4-phenylbutyrate to develop a small-molecule-basedtherapy for Alzheimer’s disease. Curr Med Chem 18, 5545-5553.

[522] Corbett GT, Roy A, Pahan K (2013) Sodium phenyl-butyrate enhances astrocytic neurotrophin synthesis viaprotein kinase C (PKC)-mediated activation of cAMP-response element-binding protein (CREB): Implications forAlzheimer disease therapy. J Biol Chem 288, 8299-8312.

[523] Barone E, Di DF, Butterfield DA (2014) Statins morethan cholesterol lowering agents in Alzheimer disease:Their pleiotropic functions as potential therapeutic targets.Biochem Pharmacol 88, 605-616.

[524] Richardson K, Schoen M, French B, Umscheid CA, MitchellMD, Arnold SE, Heidenreich PA, Rader DJ, Degoma EM

(2013) Statins and cognitive function: A systematic review.Ann Intern Med 159, 688-697.

[525] Campoy S, Sierra S, Suarez B, Ramos MC, Velasco J, Bur-gos JS, Adrio JL (2010) Semisynthesis of novel monacolinJ derivatives: Hypocholesterolemic and neuroprotectiveactivities. J Antibiot (Tokyo) 63, 499-505.

[526] Gard PR (2008) Cognitive-enhancing effects of angiotensinIV. BMC Neurosci 9 Suppl 2, S15.

[527] De Bundel D, Smolders I, Vanderheyden P, Michotte Y(2008) Ang II and Ang IV: Unraveling the mechanism ofaction on synaptic plasticity, memory, and epilepsy. CNSNeurosci Ther 14, 315-339.

[528] Stragier B, De BD, Sarre S, Smolders I, Vauquelin G, DupontA, Michotte Y, Vanderheyden P (2008) Involvement ofinsulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: A review. Heart FailRev 13, 321-337.

[529] Albiston AL, Fernando RN, Yeatman HR, Burns P, Ng L,Daswani D, Diwakarla S, Pham V, Chai SY (2010) Geneknockout of insulin-regulated aminopeptidase: Loss of thespecific binding site for angiotensin IV and age-relateddeficit in spatial memory. Neurobiol Learn Mem 93, 19-30.

[530] Andersson H, Hallberg M (2012) Discovery of inhibitorsof insulin-regulated aminopeptidase as cognitive enhancers.Int J Hypertens 2012, 789671.

[531] Albiston AL, Diwakarla S, Fernando RN, Mountford SJ,Yeatman HR, Morgan B, Pham V, Holien JK, ParkerMW, Thompson PE, Chai SY (2011) Identification anddevelopment of specific inhibitors for insulin-regulatedaminopeptidase as a new class of cognitive enhancers. BrJ Pharmacol 164, 37-47.

[532] Hallberg M (2009) Targeting the insulin-regulatedaminopeptidase/AT4 receptor for cognitive disorders. DrugNews Perspect 22, 133-139.

[533] Chai SY, Yeatman HR, Parker MW, Ascher DB, Thomp-son PE, Mulvey HT, Albiston AL (2008) Development ofcognitive enhancers based on inhibition of insulin-regulatedaminopeptidase. BMC Neurosci 9 Suppl 2, S14.

[534] Nikolaou A, Van dE I, Tourwe D, Vauquelin G, Toth G,Mallareddy JR, Poglitsch M, Van Ginderachter JA, Van-derheyden PM (2013) [3H]IVDE77, a novel radioligandwith high affinity and selectivity for the insulin-regulatedaminopeptidase. Eur J Pharmacol 702, 93-102.

[535] Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M,Marquis C, Mely J, Hugonot-Diener L, Kinet JP, DubreuilP, Moussy A, Hermine O (2011) Masitinib as an adjuncttherapy for mild-to-moderate Alzheimer’s disease: A ran-domised, placebo-controlled phase 2 trial. Alzheimers ResTher 3, 16.

[536] Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Cast-eran N, Borge L, Hajem B, Lermet A, Sippl W, Voisset E,Arock M, Auclair C, Leventhal PS, Mansfield CD, MoussyA, Hermine O (2009) Masitinib (AB1010), a potent andselective tyrosine kinase inhibitor targeting KIT. PLoS One4, e7258.

[537] Terao Y, Suzuki H, Yoshikawa M, Yashiro H, TakekawaS, Fujitani Y, Okada K, Inoue Y, Yamamoto Y, NakagawaH, Yao S, Kawamoto T, Uchikawa O (2012) Design andbiological evaluation of imidazo[1,2-a]pyridines as noveland potent ASK1 inhibitors. Bioorg Med Chem Lett 22,7326-7329.

[538] Qian W, Jin N, Shi J, Yin X, Jin X, Wang S, Cao M,Iqbal K, Gong CX, Liu F (2013) Dual-specificity tyrosinephosphorylation-regulated kinase 1A (Dyrk1A) enhancestau expression. J Alzheimers Dis 37, 529-538.


[539] MacGregor DG, Mallon AP, Harvey AL, Young L,Nimmo HG, Stone TW (2007) Group S8A serineproteases, including a novel enzyme cadeprin, inducelong-lasting, metabotropic glutamate receptor-dependentsynaptic depression in rat hippocampal slices. Eur J Neu-rosci 26, 1870-1880.

[540] Malmstrom J, Viklund J, Slivo C, Costa A, Maudet M,Sandelin C, Hiller G, Olsson LL, Aagaard A, GeschwindnerS, Xue Y, Vasange M (2012) Synthesis and structure-activityrelationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25inhibitors. Bioorg Med Chem Lett 22, 5919-5923.

[541] Dhawan G, Combs CK (2012) Inhibition of Src kinase activ-ity attenuates amyloid associated microgliosis in a murinemodel of Alzheimer’s disease. J Neuroinflammation 9, 117.

[542] Dolan BM, Duron SG, Campbell DA, Vollrath B, Shankara-narayana Rao BS, Ko HY, Lin GG, Govindarajan A, ChoiSY, Tonegawa S (2013) Rescue of fragile X syndrome phe-notypes in Fmr1 KO mice by the small-molecule PAKinhibitor FRAX486. Proc Natl Acad Sci U S A 110, 5671-5676.

[543] Nygaard HB, van Dyck CH, Strittmatter SM (2014) Fynkinase inhibition as a novel therapy for Alzheimer’s disease.Alzheimers Res Ther 6, 8.

[544] Chen H, Chan BK, Drummond J, Estrada AA, Gunzner-Toste J, Liu X, Liu Y, Moffat J, Shore D, Sweeney ZK, TranT, Wang S, Zhao G, Zhu H, Burdick DJ (2012) Discovery ofselective LRRK2 inhibitors guided by computational anal-ysis and molecular modeling. J Med Chem 55, 5536-5545.

[545] Estrada AA, Chan BK, Baker-Glenn C, Beresford A, Bur-dick DJ, Chambers M, Chen H, Dominguez SL, Dotson J,Drummond J, Flagella M, Fuji R, Gill A, Halladay J, HarrisSF, Heffron TP, Kleinheinz T, Lee DW, Pichon CE, Liu X,Lyssikatos JP, Medhurst AD, Moffat JG, Nash K, Scearce-Levie K, Sheng Z, Shore DG, Wong S, Zhang S, ZhangX, Zhu H, Sweeney ZK (2014) Discovery of highly potent,selective, and brain-penetrant aminopyrazole leucine-richrepeat kinase 2 (LRRK2) small molecule inhibitors. J MedChem 57, 921-936.

[546] Moreno JA, Halliday M, Molloy C, Radford H, Verity N,Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA,Mallucci GR (2013) Oral treatment targeting the unfoldedprotein response prevents neurodegeneration and clinicaldisease in prion-infected mice. Sci Transl Med 5, 206ra138.

[547] Scheper W, Hoozemans JJ (2013) A new PERKspective onneurodegeneration. Sci Transl Med 5, 206fs37.

[548] Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, GrantSW, Li WH, Heerding DA, Minthorn E, Mencken T, AtkinsC, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A,Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, HassellAM, Kahler KM, Shewchuk LM, Gampe RT (2012) Dis-covery of 7-methyl-5-(1-[3-(trifluoromethyl)phenyl]acetyl-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-classinhibitor of protein kinase R (PKR)-like endoplasmic retic-ulum kinase (PERK). J Med Chem 55, 7193-7207.

[549] Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ,Reiman DM, Gerber JD, Barnes CA, Alexander GE, ReimanEM, Bimonte-Nelson HA (2009) Peripheral delivery of aROCK inhibitor improves learning and working memory.Behav Neurosci 123, 218-223.

[550] Song Y, Chen X, Wang LY, Gao W, Zhu MJ (2013)Rho kinase inhibitor fasudil protects against beta-amyloid-induced hippocampal neurodegeneration in rats. CNSNeurosci Ther 19, 603-610.

[551] Schneider A, Huentelman MJ, Kremerskothen J, Duning K,Spoelgen R, Nikolich K (2010) KIBRA: A new gateway tolearning and memory? Front Aging Neurosci 2, 4.

[552] Castro-Alvarez JF, Gutierrez-Vargas J, Darnaudery M,Cardona-Gomez GP (2011) ROCK inhibition prevents tauhyperphosphorylation and p25/CDK5 increase after globalcerebral ischemia. Behav Neurosci 125, 465-472.

[553] Weintraub MK, Bisson CM, Nouri JN, Vinson BT, Eimer-brink MJ, Kranjac D, Boehm GW, Chumley MJ (2013)Imatinib methanesulfonate reduces hippocampal amyloid-beta and restores cognitive function following repeatedendotoxin exposure. Brain Behav Immun 33, 24-28.

[554] Olsson B, Legros L, Guilhot F, Stromberg K, Smith J,Livesey FJ, Wilson DH, Zetterberg H, Blennow K (2013)Imatinib treatment and Abeta42 in humans. AlzheimersDement, doi: 10.1016/j.jalz.2013.08.283

[555] Garofalo AW, Adler M, Aubele DL, Bowers S, Franzini M,Goldbach E, Lorentzen C, Neitz RJ, Probst GD, Quinn KP,Santiago P, Sham HL, Tam D, Truong AP, Ye XM, Ren Z(2013) Novel cinnoline-based inhibitors of LRRK2 kinaseactivity. Bioorg Med Chem Lett 23, 71-74.

[556] Franzini M, Ye XM, Adler M, Aubele DL, Garofalo AW,Gauby S, Goldbach E, Probst GD, Quinn KP, Santiago P,Sham HL, Tam D, Truong A, Ren Z (2013) Triazolopyri-dazine LRRK2 kinase inhibitors. Bioorg Med Chem Lett 23,1967-1973.

[557] Garofalo AW, Adler M, Aubele DL, Brigham EF, Chian D,Franzini M, Goldbach E, Kwong GT, Motter R, Probst GD,Quinn KP, Ruslim L, Sham HL, Tam D, Tanaka P, TruongAP, Ye XM, Ren Z (2013) Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors. BioorgMed Chem Lett 23, 1974-1977.

[558] Guerreiro PS, Huang Y, Gysbers A, Cheng D, Gai WP,Outeiro TF, Halliday GM (2013) LRRK2 interactions withalpha-synuclein in Parkinson’s disease brains and in cellmodels. J Mol Med (Berl) 91, 513-522.

[559] Gu GJ, Lund H, Wu D, Blokzijl A, Classon C, von EG,Landegren U, Sunnemark D, Kamali-Moghaddam M (2013)Role of individual MARK isoforms in phosphorylation oftau at Ser(262) in Alzheimer’s disease. Neuromolecular Med15, 458-469.

[560] Pinsetta FR, Taft CA, de Paula da Silva CH (2014) Structure-and ligand-based drug design of novel p38-alpha MAPKinhibitors in the fight against the Alzheimer’s disease. JBiomol Struct Dyn 32, 1047-1063.

[561] Watterson DM, Grum-Tokars VL, Roy SM, SchavockyJP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E,Saeed F, Zhang H, Staniszewski A, Pelletier JC, MinasovG, Anderson WF, Arancio O, Van Eldik LJ (2013) Devel-opment of novel chemical probes to address CNS proteinkinase involvement in synaptic dysfunction. PLoS One 8,e66226.

[562] Lonskaya I, Hebron ML, Desforges NM, Schachter JB,Moussa CE (2014) Nilotinib-induced autophagic changesincrease endogenous parkin level and ubiquitination, lead-ing to amyloid clearance. J Mol Med (Berl) 92, 373-386.

[563] Tsika E, Moore DJ (2012) Mechanisms of LRRK2-mediatedneurodegeneration. Curr Neurol Neurosci Rep 12, 251-260.

[564] Echeverria V, Burgess S, Gamble-George J, Arendash GW,Citron BA (2008) Raf inhibition protects cortical cellsagainst beta-amyloid toxicity. Neurosci Lett 444, 92-96.

[565] Tahtouh T, Elkins JM, Filippakopoulos P, Soundararajan M,Burgy G, Durieu E, Cochet C, Schmid RS, Lo DC, Delhom-mel F, Oberholzer AE, Pearl LH, Carreaux F, Bazureau JP,Knapp S, Meijer L (2012) Selectivity, cocrystal structures,


and neuroprotective properties of leucettines, a family ofprotein kinase inhibitors derived from the marine spongealkaloid leucettamine B. J Med Chem 55, 9312-9330.

[566] Burgy G, Tahtouh T, Durieu E, Foll-Josselin B, Limanton E,Meijer L, Carreaux F, Bazureau JP (2013) Chemical synthe-sis and biological validation of immobilized protein kinaseinhibitory Leucettines. Eur J Med Chem 62, 728-737.

[567] Deau E, Loidreau Y, Marchand P, Nourrisson MR, Loaec N,Meijer L, Levacher V, Besson T (2013) Synthesis of novel 7-substituted pyrido[2’,3’:4,5]furo[3,2-d]pyrimidin-4-aminesand their N-aryl analogues and evaluation of their inhibitoryactivity against Ser/Thr kinases. Bioorg Med Chem Lett 23,6784-6788.

[568] Echeverria V, Burgess S, Gamble-George J, Zeitlin R, Lin X,Cao C, Arendash GW (2009) Sorafenib inhibits nuclear fac-tor kappa B, decreases inducible nitric oxide synthase andcyclooxygenase-2 expression, and restores working mem-ory in APPswe mice. Neuroscience 162, 1220-1231.

[569] Yang Y, Wang M, Lv B, Ma R, Hu J, Dun Y, Sun S, LiG (2014) Sphingosine kinase-1 protects differentiated n2acells against Beta-amyloid25-35-induced neurotoxicity viathe mitochondrial pathway. Neurochem Res 39, 932-940.

[570] Shukla V, Skuntz S, Pant HC (2012) Deregulated cdk5 activ-ity is involved in inducing Alzheimer’s disease. Arch MedRes 43, 655-662.

[571] Shukla V, Zheng YL, Mishra SK, Amin ND, Steiner J, GrantP, Kesavapany S, Pant HC (2013) A truncated peptide fromp35, a Cdk5 activator, prevents Alzheimer’s disease pheno-types in model mice. FASEB J 27, 174-186.

[572] Smith B, Medda F, Gokhale V, Dunckley T, Hulme C (2012)Recent advances in the design, synthesis, and biologicalevaluation of selective DYRK1A inhibitors: A new avenuefor a disease modifying treatment of Alzheimer’s? ACSChem Neurosci 3, 857-872.

[573] Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T,Nguyen T, Xu Y, Todd DE, Sheppard D, Pollack S,Polesskaya O, Marker DF, Dewhurst S, Gelbard HA (2013)Discovery, synthesis, and characterization of an orallybioavailable, brain penetrant inhibitor of mixed lineagekinase 3. J Med Chem 56, 8032-8048.

[574] Helal CJ, Sanner MA, Cooper CB, Gant T, Adam M, LucasJC, Kang Z, Kupchinsky S, Ahlijanian MK, Tate B, MennitiFS, Kelly K, Peterson M (2004) Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25as a potential treatment for Alzheimer’s disease. Bioorg MedChem Lett 14, 5521-5525.

[575] Helal CJ, Kang Z, Lucas JC, Gant T, Ahlijanian MK,Schachter JB, Richter KE, Cook JM, Menniti FS, Kelly K,Mente S, Pandit J, Hosea N (2009) Potent and cellularlyactive 4-aminoimidazole inhibitors of cyclin-dependentkinase 5/p25 for the treatment of Alzheimer’s disease.Bioorg Med Chem Lett 19, 5703-5707.

[576] Ramsden N, Perrin J, Ren Z, Lee BD, Zinn N, DawsonVL, Tam D, Bova M, Lang M, Drewes G, Bantscheff M,Bard F, Dawson TM, Hopf C (2011) Chemoproteomics-based design of potent LRRK2-selective lead compoundsthat attenuate Parkinson’s disease-related toxicity in humanneurons. ACS Chem Biol 6, 1021-1028.

[577] Corneveaux JJ, Liang WS, Reiman EM, Webster JA, MyersAJ, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D,Craig DW, Coon KD, Dunckley T, Bandy D, Lee W, ChenK, Beach TG, Mastroeni D, Grover A, Ravid R, Sando SB,Aasly JO, Heun R, Jessen F, Kolsch H, Rogers J, HuttonML, Melquist S, Petersen RC, Alexander GE, Caselli RJ,Papassotiropoulos A, Stephan DA, Huentelman MJ (2010)

Evidence for an association between KIBRA and late-onsetAlzheimer’s disease. Neurobiol Aging 31, 901-909.

[578] Hofmann SG, Smits JA, Asnaani A, Gutner CA, Otto MW(2011) Cognitive enhancers for anxiety disorders. Pharma-col Biochem Behav 99, 275-284.

[579] Zhang L, Yang S, Wennmann DO, Chen Y, KremerskothenJ, Dong J (2014) KIBRA: In the brain and beyond. CellSignal 26, 1392-1399.

[580] Liu M, Poulose S, Schuman E, Zaitsev AD, Dobson B,Auerbach K, Seyb K, Cuny GD, Glicksman MA, SteinRL, Yue Z (2010) Development of a mechanism-basedhigh-throughput screen assay for leucine-rich repeat kinase2–discovery of LRRK2 inhibitors. Anal Biochem 404, 186-192.

[581] Majlath Z, Tajti J, Vecsei L (2013) Kynurenines and othernovel therapeutic strategies in the treatment of dementia.Ther Adv Neurol Disord 6, 386-397.

[582] Majlath Z, Toldi J, Vecsei L (2013) The potential role ofkynurenines in Alzheimer’s disease: Pathomechanism andtherapeutic possibilities by influencing the glutamate recep-tors. J Neural Transm, doi: 10.1007/s00702-013-1135-5

[583] Plangar I, Zadori D, Klivenyi P, Toldi J, Vecsei L(2011) Targeting the kynurenine pathway-related alterationsin Alzheimer’s disease: A future therapeutic strategy. JAlzheimers Dis 24(Suppl 2), 199-209.

[584] Stone TW, Darlington LG (2013) The kynurenine pathwayas a therapeutic target in cognitive and neurodegenerativedisorders. Br J Pharmacol 169, 1211-1227.

[585] Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, GiorginiF, Leys D, Scrutton NS (2013) Structural basis of kynurenine3-monooxygenase inhibition. Nature 496, 382-385.

[586] Dounay AB, Anderson M, Vechle BM, Campbell BM, Claf-fey MM, Evdokimov A, Evrard E, Fonseca KR, Gan XM,Ghosh S, Hayward MM, Horner W, Kim JY, McAllisterLA, Pandit J, Paradis V, Parikh VD, Reese MR, Rong S,Salafia MA, Schuyten K, Strick CA, Tuttle JB, Valentine J,Wang H, Zawadzke LE, Verhoest PR (2012) Discovery ofbrain-penetrant, irreversible kynurenine aminotransferase IIinhibitors for schizophrenia. ACS Med Chem Lett 3, 187-192.

[587] Dounay AB, Anderson M, Bechle BM, Evrard E, Gan X,Kim JY, McAllister LA, Pandit J, Rong S, Salafia MA, TuttleJB, Zawadzke LE, Verhoest PR (2013) PF-04859989 as atemplate for structure-based drug design: Identification ofnew pyrazole series of irreversible KAT II inhibitors withimproved lipophilic efficiency. Bioorg Med Chem Lett 23,1961-1966.

[588] Radmark O, Werz O, Steinhilber D, Samuelsson B (2007)5-Lipoxygenase: Regulation of expression and enzymeactivity. Trends Biochem Sci 32, 332-341.

[589] Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE,Pratico D (2012) 5-Lipoxygenase gene transfer worsensmemory, amyloid, and tau brain pathologies in a mousemodel of Alzheimer disease. Ann Neurol 72, 442-454.

[590] Chu J, Li JG, Ceballos-Diaz C, Golde T, Pratico D (2013)The influence of 5-lipoxygenase on Alzheimer’s disease-related tau pathology: In vivo and in vitro evidence. BiolPsychiatry 74, 321-328.

[591] Chu J, Pratico D (2013) 5-Lipoxygenase pharmacologicalblockade decreases tau phosphorylation in vivo: Involve-ment of the cyclin-dependent kinase-5. Neurobiol Aging 34,1549-1554.

[592] Giannopoulos PF, Chu J, Joshi YB, Sperow M, Li JG, KirbyLG, Pratico D (2014) Gene knockout of 5-lipoxygenaserescues synaptic dysfunction and improves memory in the


triple-transgenic model of Alzheimer’s disease. Mol Psychi-atry 19, 511-518.

[593] Giannopoulos PF, Joshi YB, Chu J, Pratico D (2013) The12-15-lipoxygenase is a modulator of Alzheimer’s-relatedtau pathology in vivo. Aging Cell 12, 1082-1090.

[594] Giannopoulos PF, Chu J, Joshi YB, Sperow M, Li JG, KirbyLG, Pratico D (2013) 5-lipoxygenase activating proteinreduction ameliorates cognitive deficit, synaptic dysfunc-tion, and neuropathology in a mouse model of Alzheimer’sdisease. Biol Psychiatry 74, 348-356.

[595] Joshi YB, Chu J, Pratico D (2013) Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathol-ogy in 3xTg mice. Aging Cell 12, 706-711.

[596] Giannopoulos PF, Chu J, Joshi YB, Sperow M, Li JG, KirbyLG, Pratico D (2013) 5-lipoxygenase activating proteinreduction ameliorates cognitive deficit, synaptic dysfunc-tion, and neuropathology in a mouse model of Alzheimer’sdisease. Biol Psychiatry 74, 348-356.

[597] Chu J, Lauretti E, Meco AD, Pratico D (2013) FLAP phar-macological blockade modulates metabolism of endogenoustau in vivo. Transl Psychiatry 3, e333.

[598] Giannopoulos PF, Joshi YB, Pratico D (2014) Novel lipidsignaling pathways in Alzheimer’s disease pathogenesis.Biochem Pharmacol 88, 560-564.

[599] Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS,Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S,Suh YH (2007) Minocycline attenuates neuronal cell deathand improves cognitive impairment in Alzheimer’s diseasemodels. Neuropsychopharmacology 32, 2393-2404.

[600] Noble W, Garwood C, Stephenson J, Kinsey AM, HangerDP, Anderton BH (2009) Minocycline reduces the devel-opment of abnormal tau species in models of Alzheimer’sdisease. FASEB J 23, 739-750.

[601] Noble W, Garwood CJ, Hanger DP (2009) Minocycline asa potential therapeutic agent in neurodegenerative disorderscharacterised by protein misfolding. Prion 3, 78-83.

[602] Garwood CJ, Cooper JD, Hanger DP, Noble W (2010) Anti-inflammatory impact of minocycline in a mouse model oftauopathy. Front Psychiatry 1, 136.

[603] Pontiki E, Kontogiorgis C, Xu Y, Hadjipavlou-Litina D,Luo Y (2013) New lipoxygenase inhibitors of reactive oxy-gen species production in cellular models of amyloid (A2)toxicities. J Alzheimers Dis 34, 215-230.

[604] Mackeen MM, Kramer HB, Chang KH, Coleman ML,Hopkinson RJ, Schofield CJ, Kessler BM (2010) Small-molecule-based inhibition of histone demethylation in cellsassessed by quantitative mass spectrometry. J Proteome Res9, 4082-4092.

[605] Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlos-burg JE, Pavon FJ, Serrano AM, Selley DE, Parsons LH,Lichtman AH, Cravatt BF (2009) Selective blockade of2-arachidonoylglycerol hydrolysis produces cannabinoidbehavioral effects. Nat Chem Biol 5, 37-44.

[606] Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B,Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ,Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, LichtmanAH, Cravatt BF (2010) Chronic monoacylglycerol lipaseblockade causes functional antagonism of the endocannabi-noid system. Nat Neurosci 13, 1113-1119.

[607] Chen X, Zhang J, Chen C (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against beta-amyloidinsults. Neuroscience 178, 159-168.

[608] Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, TengZ, Chen C (2012) Monoacylglycerol lipase is a therapeutictarget for Alzheimer’s disease. Cell Rep 2, 1329-1339.

[609] Cai Z (2014) Monoamine oxidase inhibitors: Promisingtherapeutic agents for Alzheimer’s disease (Review). MolMed Rep 9, 1533-1541.

[610] Helguera AM, Perez-Machado G, Cordeiro MN, Borges F(2012) Discovery of MAO-B inhibitors - present status andfuture directions part I: Oxygen heterocycles and analogs.Mini Rev Med Chem 12, 907-919.

[611] Patil PO, Bari SB, Firke SD, Deshmukh PK, Donda ST,Patil DA (2013) A comprehensive review on synthesis anddesigning aspects of coumarin derivatives as monoamineoxidase inhibitors for depression and Alzheimer’s disease.Bioorg Med Chem 21, 2434-2450.

[612] Helguera AM, Perez-Garrido A, Gaspar A, Reis J, Cagide F,Vina D, Cordeiro MN, Borges F (2013) Combining QSARclassification models for predictive modeling of humanmonoamine oxidase inhibitors. Eur J Med Chem 59, 75-90.

[613] Zheng H, Weiner LM, Bar-Am O, Epsztejn S, CabantchikZI, Warshawsky A, Youdim MB, Fridkin M (2005)Design, synthesis, and evaluation of novel bifunctionaliron-chelators as potential agents for neuroprotection inAlzheimer’s, Parkinson’s, and other neurodegenerative dis-eases. Bioorg Med Chem 13, 773-783.

[614] Youdim MB (2012) M30, a brain permeable multitargetneurorestorative drug in post nigrostriatal dopamine neuronlesion of parkinsonism animal models. Parkinsonism RelatDisord 18(Suppl 1), S151-S154.

[615] Hanagasi HA, Gurvit H, Unsalan P, Horozoglu H, TuncerN, Feyzioglu A, Gunal DI, Yener GG, Cakmur R, SahinHA, Emre M (2011) The effects of rasagiline on cognitivedeficits in Parkinson’s disease patients without dementia: Arandomized, double-blind, placebo-controlled, multicenterstudy. Mov Disord 26, 1851-1858.

[616] Onofrj M, Bonanni L, Thomas A (2008) An expert opinionon safinamide in Parkinson’s disease. Expert Opin InvestigDrugs 17, 1115-1125.

[617] Pazini AM, Gomes GM, Villarinho JG, da CC, Pinheiro F,Ferreira AP, Mello CF, Ferreira J, Rubin MA (2013) Selegi-line reverses abeta25-35-induced cognitive deficit in malemice. Neurochem Res 38, 2287-2294.

[618] Tzikas S, Schlak D, Sopova K, Gatsiou A, Stakos D,Stamatelopoulos K, Stellos K, Laske C (2014) Increasedmyeloperoxidase plasma levels in patients with Alzheimer’sdisease. J Alzheimers Dis 39, 557-564.

[619] Kerr MA, Kenny AJ (1974) The molecular weight and prop-erties of a neutral metallo-endopeptidase from rabbit kidneybrush border. Biochem J 137, 489-495.

[620] Devault A, Lazure C, Nault C, Le MH, Seidah NG, ChretienM, Kahn P, Powell J, Mallet J, Beaumont A, et al (1987)Amino acid sequence of rabbit kidney neutral endopepti-dase 24.11 (enkephalinase) deduced from a complementaryDNA. EMBO J 6, 1317-1322.

[621] Shirotani K, Tsubuki S, Iwata N, Takaki Y, Harigaya W,Maruyama K, Kiryu-Seo S, Kiyama H, Iwata H, Tomita T,Iwatsubo T, Saido TC (2001) Neprilysin degrades both amy-loid beta peptides 1-40 and 1-42 most rapidly and efficientlyamong thiorphan- and phosphoramidon-sensitive endopep-tidases. J Biol Chem 276, 21895-21901.

[622] Kanemitsu H, Tomiyama T, Mori H (2003) Humanneprilysin is capable of degrading amyloid beta peptidenot only in the monomeric form but also the pathologicaloligomeric form. Neurosci Lett 350, 113-116.

[623] Park MH, Lee JK, Choi S, Ahn J, Jin HK, Park JS, Bae JS(2013) Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment inAlzheimer’s disease mice. Brain Res 1529, 113-124.


[624] Walker JR, Pacoma R, Watson J, Ou W, Alves J, MasonDE, Peters EC, Urbina HD, Welzel G, Althage A, LiuB, Tuntland T, Jacobson LH, Harris JL, Schumacher AM(2013) Enhanced proteolytic clearance of plasma Abetaby peripherally administered neprilysin does not result inreduced levels of brain Abeta in mice. J Neurosci 33,2457-2464.

[625] Yuzwa SA, Vocadlo DJ (2014) O-GlcNAc and neurode-generation: Biochemical mechanisms and potential rolesin Alzheimer’s disease and beyond. Chem Soc Rev, doi:10.1039/C4CS00038B

[626] Kang MJ, Kim C, Jeong H, Cho BK, Ryou AL, Hwang D,Mook-Jung I, Yi EC (2013) Synapsin-1 and tau reciprocalO-GlcNAcylation and phosphorylation sites in mouse brainsynaptosomes. Exp Mol Med 45, e29.

[627] Wang P, Lazarus BD, Forsythe ME, Love DC, Krause MW,Hanover JA (2012) O-GlcNAc cycling mutants modulateproteotoxicity in Caenorhabditis elegans models of humanneurodegenerative diseases. Proc Natl Acad Sci U S A 109,17669-17674.

[628] Tang C, Welty DF (2013) A dynamic view to the modulationof phosphorylation and O-GlcNAcylation by inhibition ofO-GlcNAcase. Comput Biol Chem 45, 9-16.

[629] Graham DL, Gray AJ, Joyce JA, Yu D, O’Moore J, Carl-son GA, Shearman MS, Dellovade TL, Hering H (2013)Increased O-GlcNAcylation reduces pathological tau with-out affecting its normal phosphorylation in a mouse modelof tauopathy. Neuropharmacology 79C, 307-313.

[630] Yuzwa SA, Cheung AH, Okon M, McIntosh LP, VocadloDJ (2014) O-GlcNAc Modification of tau directly inhibitsits aggregation without perturbing the conformational prop-erties of tau monomers. J Mol Biol 426, 1736-1752.

[631] Lin C, Chen EH, Lee LY, Hsu RL, Luh FY, Yang LL,Chou CF, Huang LD, Lin CC, Chen RP (2014) Comparisonof the anti-amyloidogenic effect of O-mannosylation, O-galactosylation, and O-GalNAc glycosylation. CarbohydrRes 387, 46-53.

[632] Dorfmueller HC, Borodkin VS, Schimpl M, ShepherdSM, Shpiro NA, van Aalten DM (2006) GlcNAcstatin: Apicomolar, selective O-GlcNAcase inhibitor that modulatesintracellular O-glcNAcylation levels. J Am Chem Soc 128,16484-16485.

[633] Dorfmueller HC, Borodkin VS, Schimpl M, van Aalten DM(2009) GlcNAcstatins are nanomolar inhibitors of humanO-GlcNAcase inducing cellular hyper-O-GlcNAcylation.Biochem J 420, 221-227.

[634] Kim C, Nam DW, Park SY, Song H, Hong HS, Boo JH, JungES, Kim Y, Baek JY, Kim KS, Cho JW, Mook-Jung I (2013)O-linked beta-N-acetylglucosaminidase inhibitor attenuatesbeta-amyloid plaque and rescues memory impairment. Neu-robiol Aging 34, 275-285.

[635] Macauley MS, Whitworth GE, Debowski AW, Chin D,Vocadlo DJ (2005) O-GlcNAcase uses substrate-assistedcatalysis: Kinetic analysis and development of highlyselective mechanism-inspired inhibitors. J Biol Chem 280,25313-25322.

[636] Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ (2012)Insights into O-linked N-acetylglucosamine ([0-9]O-GlcNAc) processing and dynamics through kinetic analysisof O-GlcNAc transferase and O-GlcNAcase activity on pro-tein substrates. J Biol Chem 287, 15395-15408.

[637] Lefevre T (2012) Recall sugars, forget Alzheimer’s. NatChem Biol 8, 325-326.

[638] Yu Y, Zhang L, Li X, Run X, Liang Z, Li Y, Liu Y, LeeMH, Grundke-Iqbal I, Iqbal K, Vocadlo DJ, Liu F, Gong

CX (2012) Differential effects of an O-GlcNAcase inhibitoron tau phosphorylation. PLoS One 7, e35277.

[639] Ikura T, Ito N (2013) Peptidyl-prolyl isomerase activity ofFK506 binding protein 12 prevents tau peptide from aggre-gating. Protein Eng Des Sel 26, 539-546.

[640] Blokland A, Menniti FS, Prickaerts J (2012) PDE inhibitionand cognition enhancement. Expert Opin Ther Pat 22, 349-354.

[641] Xu Y, Zhang HT, O’Donnell JM (2011) Phosphodiesterasesin the central nervous system: Implications in mood andcognitive disorders. Handb Exp Pharmacol, 447-485.

[642] Sanderson TM, Sher E (2013) The role of phosphodi-esterases in hippocampal synaptic plasticity. Neuropharma-cology 74, 86-95.

[643] Garcia-Osta A, Cuadrado-Tejedor M, Garcia-Barroso C,Oyarzabal J, Franco R (2012) Phosphodiesterases as thera-peutic targets for Alzheimer’s disease. ACS Chem Neurosci3, 832-844.

[644] Sierksma AS, Rutten K, Sydlik S, Rostamian S, Stein-busch HW, van den Hove DL, Prickaerts J (2013) Chronicphosphodiesterase type 2 inhibition improves memory inthe APPswe/PS1dE9 mouse model of Alzheimer’s disease.Neuropharmacology 64, 124-136.

[645] Zhang C, Cheng Y, Wang H, Wang C, Wilson SP, XuJ, Zhang HT (2014) RNA interference-mediated knock-down of long-form phosphodiesterase-4D (PDE4D) enzymereverses amyloid-beta42-induced memory deficits in mice.J Alzheimers Dis 38, 269-280.

[646] Peng S, Sun H, Zhang X, Liu G, Wang G (2014) Effectsof selective phosphodiesterases-4 inhibitors on learning andmemory: A review of recent research. Cell Biochem Bio-phys, doi: 10.1007/s12013-014-9930-7

[647] Reneerkens OA, Rutten K, Akkerman S, Blokland A, Shaf-fer CL, Menniti FS, Steinbusch HW, Prickaerts J (2012)Phosphodiesterase type 5 (PDE5) inhibition improves objectrecognition memory: Indications for central and peripheralmechanisms. Neurobiol Learn Mem 97, 370-379.

[648] Hoefgen N, Grunwald C, Langen B (2012) TargetingPDE10A in schizophrenia. Drugs Future 37, 577-589.

[649] MacDonald E, Van der LH, Pocock D, Cole C, ThomasN, VandenBerg PM, Bourtchouladze R, Kleim JA (2007)A novel phosphodiesterase type 4 inhibitor, HT-0712,enhances rehabilitation-dependent motor recovery andcortical reorganization after focal cortical ischemia. Neu-rorehabil Neural Repair 21, 486-496.

[650] Giembycz MA (2008) Can the anti-inflammatory poten-tial of PDE4 inhibitors be realized: Guarded optimism orwishful thinking? Br J Pharmacol 155, 288-290.

[651] Cutshall NS, Gage JL, Wheeler TN, Little TL (2013)PDE10 inhibitors and related compositions and methods.US-2013196994 A1, Aug-01-2013-Prior. Nov-16-2012.

[652] Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, LankauHJ, Grunwald C, Fan KY, Parris K, Langen B, Egerland U,Hage T, Marquis KL, Grauer S, Brennan J, Navarra R, GrafR, Harrison BL, Robichaud A, Kronbach T, Pangalos MN,Hoefgen N, Brandon NJ (2011) Highly potent, selective,and orally active phosphodiesterase 10A inhibitors. J MedChem 54, 7621-7638.

[653] Li P (2009) Organic compounds. WO-2009075784, Jun-18-2009-Prior. Dec-06-2007.

[654] Li P, Wennogle LP, Davis R, Buckton G, Hooper M (2013)Salt crystals. WO-2013192556, Dec-27-2013-Prior. Jun-21-2012.

[655] Zhang L, Villalobos A, Beck EM, Bocan T, Chappie TA,Chen L, Grimwood S, Heck SD, Helal CJ, Hou X, Humphrey


JM, Lu J, Skaddan MB, McCarthy TJ, Verhoest PR, WagerTT, Zasadny K (2013) Design and selection parameters toaccelerate the discovery of novel central nervous systempositron emission tomography (PET) ligands and their appli-cation in the development of a novel phosphodiesterase 2APET ligand. J Med Chem 56, 4568-4579.

[656] Hu E, Ma J, Biorn C, Lester-Zeiner D, Cho R, Rumfelt S,Kunz RK, Nixey T, Michelsen K, Miller S, Shi J, Wong J,Hill Della PG, Able J, Talreja S, Hwang DR, Hitchcock SA,Porter A, Immke D, Allen JR, Treanor J, Chen H (2012)Rapid identification of a novel small molecule phosphodi-esterase 10A (PDE10A) tracer. J Med Chem 55, 4776-4787.

[657] Hu E, Kunz RK, Rumfelt S, Chen N, Burli R, Li C, AndrewsKL, Zhang J, Chmait S, Kogan J, Lindstrom M, Hitch-cock SA, Treanor J (2012) Discovery of potent, selective,and metabolically stable 4-(pyridin-3-yl)cinnolines as novelphosphodiesterase 10A (PDE10A) inhibitors. Bioorg MedChem Lett 22, 2262-2265.

[658] Hu E, Kunz RK, Rumfelt S, Andrews KL, Li C, Hitch-cock SA, Lindstrom M, Treanor J (2012) Use of structurebased design to increase selectivity of pyridyl-cinnolinephosphodiesterase 10A (PDE10A) inhibitors against phos-phodiesterase 3 (PDE3). Bioorg Med Chem Lett 22,6938-6942.

[659] Rzasa RM, Hu E, Rumfelt S, Chen N, Andrews KL, ChmaitS, Falsey JR, Zhong W, Jones AD, Porter A, Louie SW, ZhaoX, Treanor JJ, Allen JR (2012) Discovery of selective biarylethers as PDE10A inhibitors: Improvement in potency andmitigation of Pgp-mediated efflux. Bioorg Med Chem Lett22, 7371-7375.

[660] Hu E, Kunz RK, Chen N, Rumfelt S, Siegmund A, AndrewsK, Chmait S, Zhao S, Davis C, Chen H, Lester-Zeiner D,Ma J, Biorn C, Shi J, Porter A, Treanor J, Allen JR (2013)Design, optimization, and biological evaluation of novelketo-benzimidazoles as potent and selective inhibitors ofphosphodiesterase 10A (PDE10A). J Med Chem 56, 8781-8792.

[661] Lee HR, Park SY, Kim HY, Shin HK, Lee WS, Rhim BY,Hong KW, Kim CD (2012) Protection by cilostazol againstamyloid-beta(1-40)-induced suppression of viability andneurite elongation through activation of CK2alpha in HT22mouse hippocampal cells. J Neurosci Res 90, 1566-1576.

[662] Lee HR, Shin HK, Park SY, Kim HY, Lee WS, Rhim BY,Hong KW, Kim CD (2014) Attenuation of beta-amyloid-induced tauopathy via activation of CK2alpha/SIRT1:Targeting for cilostazol. J Neurosci Res 92, 206-217.

[663] Nie J, Luo Y, Huang XN, Gong QH, Wu Q, Shi JS (2010)Icariin inhibits beta-amyloid peptide segment 25-35 inducedexpression of beta-secretase in rat hippocampus. Eur J Phar-macol 626, 213-218.

[664] Zeng KW, Ko H, Yang HO, Wang XM (2010) Icariin attenu-ates beta-amyloid-induced neurotoxicity by inhibition of tauprotein hyperphosphorylation in PC12 cells. Neuropharma-cology 59, 542-550.

[665] Zeng KW, Fu H, Liu GX, Wang XM (2010) Icariin attenuateslipopolysaccharide-induced microglial activation and resul-tant death of neurons by inhibiting TAK1/IKK/NF-kappaBand JNK/p38 MAPK pathways. Int Immunopharmacol 10,668-678.

[666] Urano T, Tohda C (2010) Icariin improves memory impair-ment in Alzheimer’s disease model mice (5xFAD) andattenuates amyloid beta-induced neurite atrophy. PhytotherRes 24, 1658-1663.

[667] Jin F, Gong QH, Xu YS, Wang LN, Jin H, Li F, Li LS, MaYM, Shi JS (2014) Icariin, a phoshphodiesterase-5 inhibitor,

improves learning and memory in APP/PS1 transgenic miceby stimulation of NO/cGMP signalling. Int J Neuropsy-chopharmacol 17, 871-881.

[668] Zheng M, Qu L, Lou Y (2008) Effects of icariin combinedwith Panax notoginseng saponins on ischemia reperfusion-induced cognitive impairments related with oxidative stressand CA1 of hippocampal neurons in rat. Phytother Res 22,597-604.

[669] Wen KX (2013) Synthesis and biological evaluation of novelimidazo derivatives as selective, BBB penetrant, and orallyactive bioavailable PDE9 inhibitors. 9th AFMC Interna-tional Medicinal Chemistry Symposium, October 17-AbsP5-55.

[670] Claffey MM, Helal CJ, Verhoest PR, Kang Z, Fors KS,Jung S, Zhong J, Bundesmann MW, Hou X, Lui S, KleimanRJ, Vanase-Frawley M, Schmidt AW, Menniti F, SchmidtCJ, Hoffman WE, Hajos M, McDowell L, O’Connor RE,dougall-Murphy M, Fonseca KR, Becker SL, Nelson FR,Liras S (2012) Application of structure-based drug designand parallel chemistry to identify selective, brain penetrant,in vivo active phosphodiesterase 9A inhibitors. J Med Chem55, 9055-9068.

[671] Helal CL (2012) Identification of a brain penetrant, highlyselective phosphodiesterase 2A inhibitor for the treatmentof cognitive impairment asscociated with schizophrenia(CIAS). 244th Americal Chemical Society National Meetingand Exposition, August 19-Abs MEDI-22.

[672] Helal C, Humphrey J, Chappie T, et al. (2012) Syntheticand design strategies to discover phosphodiesterase 2Ainhibitors for the treatment of cognitive impairment associ-ated with schizophrenia (CIAS). 243rd American ChemicalSociety National Meeting and Exposition, March 28-AbsMEDI-292.

[673] Perez-Gonzalez R, Pascual C, Antequera D, Bolos M,Redondo M, Perez DI, Perez-Grijalba V, Krzyzanowska A,Sarasa M, Gil C, Ferrer I, Martinez A, Carro E (2013) Phos-phodiesterase 7 inhibitor reduced cognitive impairment andpathological hallmarks in a mouse model of Alzheimer’sdisease. Neurobiol Aging 34, 2133-2145.

[674] Puzzo D, Loreto C, Giunta S, Musumeci G, FrascaG, Podda MV, Arancio O, Palmeri A (2014) Effect ofphosphodiesterase-5 inhibition on apoptosis and beta amy-loid load in aged mice. Neurobiol Aging 35, 520-531.

[675] Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E,Perez-Roldan JM, Garcia-Barroso C, Franco R, Aguirre N,Garcia-Osta A (2011) Sildenafil restores cognitive functionwithout affecting beta-amyloid burden in a mouse model ofAlzheimer’s disease. Br J Pharmacol 164, 2029-2041.

[676] Garcia-Barroso C, Ricobaraza A, Pascual-Lucas M, UncetaN, Rico AJ, Goicolea MA, Salles J, Lanciego JL, Oyarz-abal J, Franco R, Cuadrado-Tejedor M, Garcia-Osta A(2013) Tadalafil crosses the blood-brain barrier and reversescognitive dysfunction in a mouse model of AD. Neurophar-macology 64, 114-123.

[677] Zhang J, Guo J, Zhao X, Chen Z, Wang G, Liu A, WangQ, Zhou W, Xu Y, Wang C (2013) Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowersbeta-amyloid levels and improves cognitive performance inAPP/PS1 transgenic mice. Behav Brain Res 250, 230-237.

[678] Smith SM, Uslaner JM, Cox CD, Huszar SL, Cannon CE,Vardigan JD, Eddins D, Toolan DM, Kandebo M, Yao L,Raheem IT, Schreier JD, Breslin MJ, Coleman PJ, Renger JJ(2013) The novel phosphodiesterase 10A inhibitor THPP-1has antipsychotic-like effects in rat and improves cognitionin rat and rhesus monkey. Neuropharmacology 64, 215-223.


[679] Bruno O, Fedele E, Prickaerts J, Parker LA, Canepa E,Brullo C, Cavallero A, Gardella E, Balbi A, DomenicottiC, Bollen E, Gijselaers HJ, Vanmierlo T, Erb K, LimebeerCL, Argellati F, Marinari UM, Pronzato MA, RicciarelliR (2011) GEBR-7b, a novel PDE4D selective inhibitor thatimproves memory in rodents at non-emetic doses. Br J Phar-macol 164, 2054-2063.

[680] Sierksma AS, van den Hove DL, Pfau F, Philippens M,Bruno O, Fedele E, Ricciarelli R, Steinbusch HW, VanmierloT, Prickaerts J (2014) Improvement of spatial memory func-tion in APPswe/PS1dE9 mice after chronic inhibition ofphosphodiesterase type 4D. Neuropharmacology 77, 120-130.

[681] Yagami T, Yamamoto Y, Koma H (2014) The role of secre-tory phospholipase A2 in the central nervous system andneurological diseases. Mol Neurobiol 49, 863-876.

[682] Schaeffer EL, De-Paula VJ, da Silva ER, de AN, Skaf HD,Forlenza OV, Gattaz WF (2011) Inhibition of phospholipaseA2 in rat brain decreases the levels of total Tau protein. JNeural Transm 118, 1273-1279.

[683] Shaddinger BC, Xu Y, Roger JH, Macphee CH, HandelM, Baidoo CA, Magee M, Lepore JJ, Sprecher DL (2014)Platelet aggregation unchanged by lipoprotein-associatedphospholipase A2 inhibition: Results from an in vitro studyand two randomized phase I trials. PLoS One 9, e83094.

[684] Acharya NK, Levin EC, Clifford PM, Han M, TourtellotteR, Chamberlain D, Pollaro M, Coretti NJ, Kosciuk MC,Nagele EP, DeMarshall C, Freeman T, Shi Y, Guan C,Macphee CH, Wilensky RL, Nagele RG (2013) Diabetesand hypercholesterolemia increase blood-brain barrier per-meability and brain amyloid deposition: Beneficial effectsof the LpPLA2 inhibitor darapladib. J Alzheimers Dis 35,179-198.

[685] Oh SB, Byun CJ, Yun JH, Jo DG, Carmeliet P, Koh JY, LeeJY (2014) Tissue plasminogen activator arrests Alzheimer’sdisease pathogenesis. Neurobiol Aging 35, 511-519.

[686] Weng SC, Shu KH, Tang YJ, Sheu WH, Tarng DC, WuMJ, Chen YM, Chuang YW (2012) Progression of cognitivedysfunction in elderly chronic kidney disease patients in aveteran’s institution in central Taiwan: A 3-year longitudinalstudy. Intern Med 51, 29-35.

[687] Cho H, Joo Y, Kim S, Woo RS, Lee SH, Kim HS (2013)Plasminogen activator inhibitor-1 promotes synaptogenesisand protects against abeta(1-42)-induced neurotoxicity inprimary cultured hippocampal neurons. Int J Neurosci 123,42-49.

[688] Russo AL, Kwon HC, Burgan WE, Carter D, Beam K,Weizheng X, Zhang J, Slusher BS, Chakravarti A, Tofilon PJ,Camphausen K (2009) In vitro and in vivo radiosensitizationof glioblastoma cells by the poly (ADP-ribose) polymeraseinhibitor E7016. Clin Cancer Res 15, 607-612.

[689] Vangavaragu JR, Valasani KR, Gan X, Yan SS (2014) Iden-tification of human presequence protease (hPreP) agonistsfor the treatment of Alzheimer’s disease. Eur J Med Chem76, 506-516.

[690] Hannula MJ, Myohanen TT, Tenorio-Laranga J, MannistoPT, Garcia-Horsman JA (2013) Prolyl oligopeptidase colo-calizes with alpha-synuclein, beta-amyloid, tau protein andastroglia in the post-mortem brain samples with Parkinson’sand Alzheimer’s diseases. Neuroscience 242, 140-150.

[691] van der Veken P, Fulop V, Rea D, Gerard M, VanER, Joossens J, Cheng JD, Baekelandt V, De M,Lambeir I, Augustyns AM, K (2012) P2-substituted N-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase:Biochemical evaluation, binding mode determination, and

assessment in a cellular model of synucleinopathy. J MedChem 55, 9856-9867.

[692] Akitake Y, Nakatani Y, Kamei D, Hosokawa M, AkatsuH, Uematsu S, Akira S, Kudo I, Hara S, Takahashi M(2013) Microsomal prostaglandin E synthase-1 is induced inAlzheimer’s disease and its deletion mitigates Alzheimer’sdisease-like pathology in a mouse model. J Neurosci Res 91,909-919.

[693] Cho D, Lee H, Shin J, et al. (2011) Dose escalation study toinvestigate the safety, tolerability and pharmacokinetics ofAAD-2004, a potent spin trapping molecule and microsomalprostaglandin E synthase-1 inhibitor, in healthy Korean malevolunteers. 112th American Society for Clinical Pharmacol-ogy and Therapeutics Annual Meeting, March 04-LBII-3.

[694] Nakagawa Y, Yanagita RC, Hamada N, Murakami A,Takahashi H, Saito N, Nagai H, Irie K (2009) A simpleanalogue of tumor-promoting aplysiatoxin is an antineo-plastic agent rather than a tumor promoter: Developmentof a synthetically accessible protein kinase C activator withbryostatin-like activity. J Am Chem Soc 131, 7573-7579.

[695] Nakagawa Y, Kikumori M, Yanagita RC, Murakami A,Tokuda H, Nagai H, Irie K (2011) Synthesis and biologicalevaluation of the 12,12-dimethyl derivative of Aplog-1, ananti-proliferative analog of tumor-promoting aplysiatoxin.Biosci Biotechnol Biochem 75, 1167-1173.

[696] Irie K, Yanagita RC, Nakagawa Y (2012) Challenges to thedevelopment of bryostatin-type anticancer drugs based onthe activation mechanism of protein kinase Cdelta. Med ResRev 32, 518-535.

[697] Luo S, Lan T, Liao W, Zhao M, Yang H (2012) Genisteininhibits Abeta(25-35)-induced neurotoxicity in PC12 cellsvia PKC signaling pathway. Neurochem Res 37, 2787-2794.

[698] Patrignani C, Magnone MC, Tavano P, Ardizzone M, MuzioV, Greco B, Zaratin PF (2008) Knockout mice reveal a rolefor protein tyrosine phosphatase H1 in cognition. BehavBrain Funct 4, 36.

[699] Gagnon KT (2010) HD Therapeutics – CHDI Fifth AnnualConference. IDrugs 13, 219-223.

[700] Friesland A, Zhao Y, Chen YH, Wang L, Zhou H, Lu Q(2013) Small molecule targeting Cdc42-intersectin interac-tion disrupts Golgi organization and suppresses cell motility.Proc Natl Acad Sci U S A 110, 1261-1266.

[701] Geekiyanage H, Chan C (2011) MicroRNA-137/181c reg-ulates serine palmitoyltransferase and in turn amyloid beta,novel targets in sporadic Alzheimer’s disease. J Neurosci31, 14820-14830.

[702] Geekiyanage H, Upadhye A, Chan C (2013) Inhibition ofserine palmitoyltransferase reduces Abeta and tau hyper-phosphorylation in a murine model: A safe therapeuticstrategy for Alzheimer’s disease. Neurobiol Aging 34, 2037-2051.

[703] Langley B, Sauve A (2013) Sirtuin deacetylases as thera-peutic targets in the nervous system. Neurotherapeutics 10,605-620.

[704] Min SW, Sohn PD, Cho SH, Swanson RA, Gan L (2013) Sir-tuins in neurodegenerative diseases: An update on potentialmechanisms. Front Aging Neurosci 5, 53.

[705] Duan W (2013) Sirtuins: From metabolic regulation to brainaging. Front Aging Neurosci 5, 36.

[706] Godoy JA, Zolezzi JM, Braidy N, Inestrosa NC (2014)Role of Sirt1 during the ageing process: Relevance toprotection of synapses in the brain. Mol Neurobiol, doi:10.1007/s12035-014-8645-5

[707] Du LL, Xie JZ, Cheng XS, Li XH, Kong FL, Jiang X,Ma ZW, Wang JZ, Chen C, Zhou XW (2014) Activation


of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries inrat hippocampi. Age (Dordr) 36, 613-623.

[708] Varamini B, Sikalidis AK, Bradford KL (2014) Resveratrolincreases cerebral glycogen synthase kinase phosphoryla-tion as well as protein levels of drebrin and transthyretin inmice: An exploratory study. Int J Food Sci Nutr 65, 89-96.

[709] Porquet D, Casadesus G, Bayod S, Vicente A, Canudas AM,Vilaplana. J, Pelegri C, Sanfeliu C, Camins A, Pallas M, delVJ (2013) Dietary resveratrol prevents Alzheimer’s markersand increases life span in SAMP8. Age (Dordr) 35, 1851-1865.

[710] Frozza RL, Bernardi A, Hoppe JB, Meneghetti AB, Bat-tastini AM, Pohlmann AR, Guterres SS, Salbego C (2013)Lipid-core nanocapsules improve the effects of resveratrolagainst Abeta-induced neuroinflammation. J Biomed Nan-otechnol 9, 2086-2104.

[711] Lu C, Guo Y, Li J, Yao M, Liao Q, Xie Z, Li X (2012)Design, synthesis, and evaluation of resveratrol derivativesas Ass((1)-(4)(2)) aggregation inhibitors, antioxidants, andneuroprotective agents. Bioorg Med Chem Lett 22, 7683-7687.

[712] Lu C, Guo Y, Yan J, Luo Z, Luo HB, Yan M, HuangL, Li X (2013) Design, synthesis, and evaluation ofmultitarget-directed resveratrol derivatives for the treatmentof Alzheimer’s disease. J Med Chem 56, 5843-5859.

[713] Napper AD, Hixon J, McDonagh T, Keavey K, Pons JF,Barker J, Yau WT, Amouzegh P, Flegg A, Hamelin E,Thomas RJ, Kates M, Jones S, Navia MA, Saunders JO, DiS-tefano PS, Curtis R (2005) Discovery of indoles as potentand selective inhibitors of the deacetylase SIRT1. J MedChem 48, 8045-8054.

[714] Mellini P, Carafa V, Di RB, Rotili D, De VD, Cirilli R,Gallinella B, Provvisiero DP, Di MS, Novellino E, AltucciL, Mai A (2012) Carprofen analogues as sirtuin inhibitors:Enzyme and cellular studies. Chem Med Chem 7, 1905-1908.

[715] Smith MR, Syed A, Lukacsovich T, Purcell J, BarbaroBA, Worthge SA, Wei SR, Pollio G, Magnoni L, ScaliC, Massai L, Franceschini D, Camarri M, Gianfriddo M,Diodato E, Thomas R, Gokce O, Tabrizi SJ, CaricasoleA, Landwehrmeyer B, Menalled L, Murphy C, Ramboz S,Luthi-Carter R, Westerberg G, Marsh JL (2014) A potentand selective Sirtuin 1 inhibitor alleviates pathology in mul-tiple animal and cell models of Huntington’s disease. HumMol Genet 23, 2995-3007.

[716] Stergiakouli E, Langley K, Williams H, Walters J, WilliamsNM, Suren S, Giegling I, Wilkinson LS, Owen MJ,O’Donovan MC, Rujescu D, Thapar A, Davies W (2011)Steroid sulfatase is a potential modifier of cognition in atten-tion deficit hyperactivity disorder. Genes Brain Behav 10,334-344.

[717] Zhu L, Zhong M, Zhao J, Rhee H, Caesar I, Knight EM,Volpicelli-Daley L, Bustos V, Netzer W, Liu L, LucastL, Ehrlich ME, Robakis NK, Gandy SE, Cai D (2013)Reduction of synaptojanin 1 accelerates abeta clearance andattenuates cognitive deterioration in an Alzheimer mousemodel. J Biol Chem 288, 32050-32063.

[718] McIntire LB, Berman DE, Myaeng J, Staniszewski A, Aran-cio O, Di PG, Kim TW (2012) Reduction of synaptojanin1 ameliorates synaptic and behavioral impairments in amouse model of Alzheimer’s disease. J Neurosci 32, 15271-15276.

[719] McIntire LB, Lee KI, Chang-Ileto B, Di PG, Kim TW (2014)Screening assay for small-molecule inhibitors of synapto-

janin 1, a synaptic phosphoinositide phosphatase. J BiomolScreen 19, 585-594.

[720] Wilhelmus MM, de Jager M., Bakker EN, Drukarch B(2014) Tissue transglutaminase in Alzheimer’s disease:Involvement in pathogenesis and its potential as a thera-peutic target. J Alzheimers Dis, doi: 10.3233/JAD-132492

[721] Wilhelmus MM, Drukarch B (2014) Tissue transglutam-inase is a biochemical marker for Alzheimer’s disease.Neurobiol Aging 35, e3-e4.

[722] Prime ME, Andersen OA, Barker JJ, Brooks MA, ChengRK, Toogood-Johnson I, Courtney SM, Brookfield FA,Yarnold CJ, Marston RW, Johnson PD, Johnsen SF, Pal-frey JJ, Vaidya D, Erfan S, Ichihara O, Felicetti B, Palan S,Pedret-Dunn A, Schaertl S, Sternberger I, Ebneth A, ScheelA, Winkler D, Toledo-Sherman L, Beconi M, Macdonald D,Munoz-Sanjuan I, Dominguez C, Wityak J (2012) Discov-ery and structure-activity relationship of potent and selectivecovalent inhibitors of transglutaminase 2 for Huntington’sdisease. J Med Chem 55, 1021-1046.

[723] Ramanan VK, Risacher SL, Nho K, Kim S, SwaminathanS, Shen L, Foroud TM, Hakonarson H, Huentelman MJ,Aisen PS, Petersen RC, Green RC, Jack CR, Koeppe RA,Jagust WJ, Weiner MW, Saykin AJ (2014) APOE and BCHEas modulators of cerebral amyloid deposition: A florbetapirPET genome-wide association study. Mol Psychiatry 19,351-357.

[724] Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ(2009) Efficacy and safety of natural acetylcholinesteraseinhibitor huperzine A in the treatment of Alzheimer’s dis-ease: An updated meta-analysis. J Neural Transm 116,457-465.

[725] Ma X, Tan C, Zhu D, Gang DR, Xiao P (2007) HuperzineA from Huperzia species–an ethnopharmacolgical review. JEthnopharmacol 113, 15-34.

[726] Liang YQ, Tang XC (2006) Comparative studies ofhuperzine A, donepezil, and rivastigmine on brainacetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine levels in freely-moving rats. ActaPharmacol Sin 27, 1127-1136.

[727] Liang YQ, Tang XC (2004) Comparative effects ofhuperzine A, donepezil and rivastigmine on cortical acetyl-choline level and acetylcholinesterase activity in rats.Neurosci Lett 361, 56-59.

[728] Gordon RK, Nigam SV, Weitz JA, Dave JR, Doctor BP,Ved HS (2001) The NMDA receptor ion channel: A sitefor binding of Huperzine A. J Appl Toxicol 21(Suppl 1),S47-S51.

[729] Saeed A, Mahesar PA, Zaib S, Khan MS, Matin A, Shahid M,Iqbal J (2014) Synthesis, cytotoxicity and molecular mod-elling studies of new phenylcinnamide derivatives as potentinhibitors of cholinesterases. Eur J Med Chem 78, 43-53.

[730] Xu ZC, Wang XB, Yu WY, Xie SS, Li SY, Kong LY(2014) Design, synthesis and biological evaluation of ben-zylisoquinoline derivatives as multifunctional agents againstAlzheimer’s disease. Bioorg Med Chem Lett 24, 2368-2373.

[731] Liu J, Qiu J, Wang M, Wang L, Su L, Gao J, GuQ, Xu J, Huang SL, Gu LQ, Huang ZS, Li D (2014)Synthesis and characterization of 1H-Phenanthro[9,10-d]imidazole derivatives as multifunctional agents fortreatment of Alzheimer’s disease. Biochim Biophys Acta,http://dx.doi.org/10.1016/j.bbagen.2014.05.005

[732] Kandalepas PC, Vassar R (2014) The normal and patho-logic roles of the Alzheimer’s beta-secretase, BACE1. CurrAlzheimer Res, 2014 Jun 4. [Epub ahead of print]-PMID:24893886.


[733] Tian L, Zhang K, Tian ZY, Wang T, Shang DS, Li B, Liu DX,Fang WG, Wang ZY, Chen YH (2014) Decreased expressionof cathepsin D in monocytes is related to the defective degra-dation of amyloid-beta in Alzheimer’s disease. J AlzheimersDis, doi: 10.3233/JAD-132192

[734] Sun JH, Yu JT, Tan L (2014) The role of cholesterolmetabolism in Alzheimer’s disease. Mol Neurobiol, doi:10.1007/s12035-014-8749-y

[735] Allinquant B, Clamagirand C, Potier MC (2014)Role of cholesterol metabolism in the pathogenesis ofAlzheimer’s disease. Curr Opin Clin Nutr Metab Care, doi:10.1097/MCO.0000000000000069

[736] Bayer TA, Wirths O (2014) Focusing the amyloid cas-cade hypothesis on N-truncated Abeta peptides as drugtargets against Alzheimer’s disease. Acta Neuropathol, doi:10.1007/s00401-014-1287-x

[737] Matos JO, Goldblatt G, Jeon J, Chen B, Tatulian SA (2014)Pyroglutamylated amyloid-beta peptide reverses cross beta-sheets by a prion-like mechanism. J Phys Chem B, doi:10.1021/jp412743s

[738] Zhang LL, Sui HJ, Liang B, Wang HM, Qu WH, Yu SX,Jin Y (2014) Atorvastatin prevents amyloid-beta peptideoligomer-induced synaptotoxicity and memory dysfunctionin rats through a p38 MAPK-dependent pathway. Acta Phar-macol Sin, doi: 10.1038/aps.2013.203

[739] Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG (2014)Distinct patterns of sirtuin expression during progression ofAlzheimer’s disease. Neuromolecular Med 16, 405-414.

[740] Sun Q, Jia N, Wang W, Jin H, Xu J, Hu H (2014) Acti-vation of SIRT1 by curcumin blocks the neurotoxicity ofamyloid-beta25-35 in rat cortical neurons. Biochem BiophysRes Commun 448, 89-94.

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