DesignandDevelopmentofCNSDrugs

Paul F. Jackson, Ph.D.

Outline

•  Neurologicaldisorders•  Thebrainandbloodbrainbarrier•  Strategiestogetcompoundsintothebrain

KeyConcepts

•  WhatisrequiredtodevelopCNSdrugs•  Whataresomeofthemethodsusedtogetcompoundsintothebrain

NeurologicalDisordersRequiringCentrally-ac=veDrugs

DepressionAnxietydisordersSchizophreniaBipolardisorderParkinson’sdiseaseSeizuredisordersAlzheimer’sdiseaseStroke

CentralNervousSystemDrugDiscovery

•  Approximately7000drugsintheComprehensiveMedicinalChemistrydatabase

•  Only5%treatCNSdisorders•  Physiologicalchallengesfordrugtogetintothebrain•  FailurerateofCNSdrugsishigherthanaverage•  TimefromentryintoFIHtoapprovalislonger

DrugDistribu=onofCentrally-ac=veTherapies ~2%ofSMentersthebrain

Maxmorpharma.com

TheBloodBrainBarrier•  1885-EhrlichreportsthatparentalinjecUonofdyesdistribute

toallorgansexceptthebrainandspinalcord.•  1898-BieldandKraussuggestthatthereisabarrieraroundthe

brain•  1900-LewandowskyshowsthatinjecUonofcholicacidsor

sodiumferrocyanidehadnoCNSeffects;coinedthephrase“bloodbrainbarrier”toexplaintheeffects.

•  1967–EMstudiesshowtheexistenceofastructuralbarrieraroundthebrain

TheBloodBrainBarrierFunc=on

•  ControlsthemovementofmoleculesintoandoutoftheCNS•  AllowsforcontrolofthecomposiUonoftheintersUUalfluid•  MaintainssynapUcfuncUoningandneuronalconnecUvity•  ProtectstheCNSfromtoxinsandinflammaUon•  BreakdownintheBBBisseeninseveraldiseasesincluding

Parkinson’sdisease,Alzheimer'sdisease,andHIV-1associateddemenUa

Sweeney,M.etal.NatureReviews:Neurology,2018Daneman,R.etal.ColdSpringHarb.PerspecUve.Biol.,2015,7,1-23

HowDoCompoundsGetintotheBrain?

•  PassiveDiffusion–  Lowmolecularweightandhighlipophilicity

•  AcUvetransport–  UUlizestransportproteins

•  Endocytosis

Nanomedicine.2012;7(8):1225-1233

PassiveDiffusion-Howdomedicinalchemists

op=mizemoleculestogetintothebrain

KeyPhysicochemicalParameters

•  logP–  Measureoflipophilicity;parUoncoefficientbetweenanaqueousand

lipophilicphase,usuallywaterandoctanol–  Hansch–1967-ParabolicrelaUonshipbetweenlogPandhypnoUc

acUvity–  OpUmallogPofapproximately2forCNSacUvity–  RefinedtoshowtheopUmalvalueforavarietyofCNSacUvemolecules

is2.4

BrainLevels

logP

ExampleoflogPandBrainLevels

OtherRelevantPhysicochemicalParameters•  logD

–  pHdependent;bemerdescriptorsincemostCNSmoleculeshavebasicgroups

–  logDshouldbebetween0and3•  HydrogenBonding

–  IncreasedHbondingcapacityisassociatedwithlowerpermeability–  AlsoincreasestheriskofP-gprecogniUon–  Hydrogenbonddonors<3,Hydrogenbondacceptors<7,totalH-

bonds<8•  PolarSurfaceArea

–  Measureofsurfaceareaoverallpolaratoms–  CalculatedasTPSA–  ForaCNScompounditshouldbebelow70

•  MolecularFlexibilityandRota;onalBonds–  IncreasedmolecularflexibilityexertsanegaUveeffectonbrain

penetraUon–  Rotatablebonds<8

PhysicochemicalParameters

•  pKa–  MostCNScompoundscontainachargedgroup–  pKaaround8.4isop=mal

•  MolecularWeight–  IncreasedMWwillleadtodecreasingbrainpenetraUon–  MW<450

Mul=parameterOp=miza=on(MPO)

•  CNSMPO(Pfizer,2010)•  LogDandMWarebemerpredictorsthanlogDalone•  DevelopedscoringfuncUonsthatcombinemulUpleparameters

intoasinglevalue•  UseclogP,clogD,MW,TPSA,HBDcount,andpKa•  Assignavalueof0-1foreachpropertywith0being

undesirableand1beinghighlydesirable•  74%ofCNSdrugsaregreaterthanorequalto4

DrugDiscoveryToday2017,22,965-969J.Med.Chem.2017,60,5943,5943-5954ACSChem.Neurosci.2010,1,435-449

TopPrescribedCNSDrugs

EffluxTransporters•  Severaltypesofeffluxreceptorsareexpressedonbrain

capillaryendothelialcells•  HighlevelofATP-bindingcasseme(ABC)transporters

–  MostwidelystudiedandcharacterizedaretheP-glycoproteins(P-gp)–  12transmembraneprotein;1280aminoacids

•  Responsibleforpumpingmoleculesoutofthebrain•  LargenumberofsmallmoleculesareP-gpsubstrates•  Furtherlimitstheaccessibilityofsmallmoleculestotargetsin

thebrain

ALSTherapyDevelopmentInsUtute

AssaystoHelpPredictBrainLevelsNeuroPK-Measurethelevelsofadruginthebrainandcompareittoplasmalevels-Needtoexaminefreevsbounddrug-RaUoofunbounddruginbraintounbounddruginplasma,Kp,uu

•  IfraUois1,goodpassivepermeability•  IfraUoislessthan1,substrateforaneffluxtransporter•  IfraUoisgreaterthan1aninfluxtransporterisinvolved

J.Med.Chem.2013,56,2-12

AssaystoHelpPredictBrainLevels

•  Microdialysiscanbeusedtoseeifacompoundisinthebrain– Usuallyusedononlyafewcompoundswithinaseries

•  PETimaging•  P-gpknockoutmicetodetermineefflux

ExamplesofDesigningCompoundsThatGetintotheBrain

Schizophrenia•  Chronicmentalillnessthateffects0.5–1.0%ofthepopulaUon•  SymptomsareclassifiedasposiUve,negaUve,orcogniUve

–  PosiUve–  NegaUve–  CogniUve

BipolarDisorders,2015hmp://bipolarsymptoms.com/schizophrenia-symptoms/

ExamplesofDesigningCompoundsThatGetintotheBrain

Schizophrenia•  MajorityofdrugsfocusondopaminergicreceptorssuchasD2

andserotoninreceptor5-HT2a.

•  Approacheshaveemergedthatinvolvenon-dopaminergic

receptorsResearchDirecUonsinSchizophreniaTreatment:MechanismsofAcUonforNext-GeneraUonAgentshmps://www.medscape.org

Firstgenera=onvssecondgenera=onan=psycho=cs

•  FirstgeneraUon(typical)medicaUons–  Focusedondopamineantagonism–  EffecUveagainsttheposiUveeffectsofschizophrenia–  Duetoinvolvementofdopamineinmovementmayhavemotorsideeffects

•  SecondgeneraUon(atypical)medicaUons–  Focusonnon-dopaminergicpathways–  HaveeffectsonnegaUvesymptoms–  Sideeffectprofileismorefavorable

Phosphodiesterase10Inhibitors

•  PDE10Ahighlyexpressedinthemediumneuronofthestriatumwhichistheregionmostassociatedwithschizophrenia

•  PDE10inhibitorsmaybeusefultreaUngallthreemajorsymptomsofschizophrenia

•  TargetscAMPandcGMPandnotdopamine•  PotenUallydevoidofsomeofthesideeffectsassociatedwith

agentsdirectlyacUngondopaminergicreceptors

PDE10Inhibitors-ReducingHBD

HBD=3Poorbrainexposure

HBD=2

HBD=1Increasebrainlevels

J.Med.Chem.2013,56,8781-8792

PDE10Inhibitors-ReducingPSAandEffluxoutofbrain

TPSA=91ER=6.2

Biorg.Med.Chem.Lem,2015,23,7138-7149

TPSA=82ER=2.0

TPSA=65ER=0.56

α7Nico=nicAcetylcholineReceptorAgonists

•  NeuronalnicoUnicacetylcholinereceptors-ligandgatedionchannels.

•  α7NicoUnicacetylcholinereceptorisoneofthemostabundantsubtypesfoundinthebrain.

•  Highlyexpressedinthecerebralcortexandhippocampus.•  ReducedexpressionofthereceptorinbrainUssuefrom

schizophreniapaUents•  MayhelpwithcogniUveandnegaUvesymptomsof

schizophrenia

α7Nico=nicAcetylcholineReceptorAgonists–Modula=onofpKa

Kalmady,SunilV.JournalofNeuralTransmission,2018.CHRFAM7Ageneexpressioninschizophrenia:clinicalcorrelatesandtheeffectofanUpsychoUctreatmentBMCL,2013,23,1684–1688

Prodrugs

EfficientDeliveryofRNAiProdrugs,igtrcn.org

Prodrugs•  BioreversiblederivaUvesofdrugmoleculesthatundergoa

chemicalorenzymaUcbiotransformaUontotheacUveformswithinthebody

•  OvercomespharmacokineUclimitaUonsofparentdrug•  Chemicallymodifyadrugtobecomemorelipophilic•  SpecifictypeusedinCNSresearchisachemicaldelivery

system(CDS)•  IncreaselipophilicityandlockscompoundintobrainprevenUng

itfromcomingbackoutviaeffluxmechanism

Prodrugs–ExampleofaCDS•  Deliveryofacetylcholinesteraseinhibitor

–  CurrentdrugsareusedforthesymptomaUctreatmentofcogniUveeffectsinAlzheimer’sdisease

–  EliminateperipheralcholinergicacUvity

•  Deliveryofabrainimagingagent

ACSChem.Neurosci.2017,8,2457-2467ACSChem.Neurosci.2015,6,737-744

Prodrugs–ExampleofUsingaBrainEnzymeforAc=va=on

•  ProdrugfordeliveryofthyromimeUcsobeUrome•  UUlizefamyacidamidehydrolase(FAAH)•  MaybebeneficialinMS,•  EliminateperipheralthyroidacUvity

•  50-foldincreaseinbrainlevelsACSChem.Neurosci.2017,8,2468-2476

Ac=veTransport-Howdomedicinalchemists

op=mizemoleculestogetintothebrain

BioImpacts,2012,2,5-22

ExampleofaDrugUsingtheTransporterLAT1

•  Parkinson’sdiseaseischaracterizedbyalowlevelofdopamine•  Dopaminewillnotcrossthebloodbrainbarrier•  1967L-Dopaisapproved•  ArvidCarlsonNobelprize2000;WilliamKnowlesNobelPrize

2001

ExampleofConjuga=ngaDrugtoaLAT1Substrate

•  Ketoprofen–NeuroinflamaUon•  Valproicacid–SeizureDisorders

J.Contr.Rel.,2017,261,93-104Mol.PharmaceuUcs,2011,8,1857-1866J.Med.Chem.,2008,51,932-936

ExampleofConjuga=ngaDrugtoGlucoseandVitaminCtransporters

•  UUlizetransportersforglucoseandtransporterforvitaminC•  Releaseibuprofeninthebrain•  DualtargeUngprodrugshowedneuroprotecUveeffect

comparedwithcontrol

DrugDelivery,2018,25,426-434

ReceptorMediatedTransport•  CertainlargemoleculepepUdesinthebloodundergoreceptor

mediatedtransportacrosstheBBBviaendogenouspepUdereceptors

•  InsulinusestheBBBinsulinreceptor•  TransferrinistransportedacrosstheBBusingtheendogenous

transferrinreceptor•  MolecularTrojanHorsetechnology(MTH)uUlizestheseand

relatedsystemstotransportmoleculesintothebrain

ReceptorMediatedTransport•  Parkinson’sDisease

–  Glial-derivedneurotrophicfactor(GDNF)isaproteinthatpromotesthesurvivalofdopaminergicneurons

–  Doesnotgetintothebrain–  FusionproteinofGDNFcoupledwiththetransferrinrecogniUonanUbody

–  SignificantimprovementinthreemodelsofPD

•  Epilepsy,Pain–  Metabotropicglutamatereceptor-1–  AnUbodyantagonistofmGluR1coupledtoasingle-domainanUbody–  20-foldincreaseinbrainlevels

TheFASEBJournal2017,30,1927-1940ClinicalPharm.andTherap.2015,97,347-361

Othermechanismstogetcompoundsintothebrain

Alterna=veApproaches•  Cyclodextrins

–  Consistofcyclicoligosaccharides

–  Modifyeffluxofdrugs–  TightjuncUons

•  P-glycoproteininhibitors•  Nosetobraindelivery•  DisrupUonofthebloodbrainbarrier

Kung,Y.etal.ScienUficReports,2018,2218

Nanotechnology•  Nanomedicine2017,12,237-253

•  Ironcoatedliposomescontainingnimodipine•  EfficaciousinanimalmodelsofParkinson’sDisease

•  J.Con.Rel.2017,246,96-109•  NanoparUclecontainingdocetaxelforthetreatmentofbrainmetastaUcbreastcancer

•  CoatedthesurfaceofthenanoparUclewithpolysorbate80(LDLmediatedtransport)

Nanotechnology•  Eur.J.Pharm.Sci.,2018,115,77-87

•  PLCL(polymer)nanoparUclescontaininglamotrigine•  Usedtotreatepilepsyandbipolardisorder

•  Observehighlevelsinthebrain•  CantunebyalteringthecomposiUonofthepolymer

UsingtheBBBtopreventamoleculefromexer=ngitseffect

•  Receptorsforcertaindrugsmaynotberestrictedtothebrain•  Whatdoyoudoifyouwanttokeepamoleculeoutofthe

brain?•  Rimonabant–selecUveCB1Antagonistforweightloss•  SeriousCNSsideeffects

DrugDisc.Today,2018,Shrestha,N.etal.January,onlineinpress

Summary•  Thebloodbrainbarrierpreventsmostsmallmoleculesfromenteringthebrain

•  ChemistshaveavarietyofpredicUvetoolsthattheyemploytodesigncompoundsthatcangetintothebrain

•  TransporterscanbeuUlizedtoshumledrugsintothebrain

•  NewmethodsinvolvingfusionofanUbodies,nosetobraintechnologies,andnanotechnologywillaidinthefuturedeliveryofdrugs

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