[Handbook of Experimental Pharmacology] Adenosine Receptors in Health and Disease Volume 193 ||...

Recent Developments in A2B AdenosineReceptor Ligands

Rao V. Kalla, Jeff Zablocki, Mojgan Aghazadeh Tabrizi,and Pier Giovanni Baraldi

Contents

1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 A2B Adenosine Receptor Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

2.1 Xanthine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022.2 Deazaxanthine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092.3 Adenine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112.4 2-Aminopyridine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122.5 Bipyrimidine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132.6 Pyrimidone-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1142.7 Imidazopyridine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1142.8 Pyrazine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152.9 Pyrazolo-Triazolo-Pyrimidine-Based Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

3 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

Abstract A selective, high-affinity A2B adenosine receptor (AR) antagonist willbe useful as a pharmacological tool to help determine the role of the A2BAR in in-flammatory diseases and angiogenic diseases. Based on early A2BAR-selectiveligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754:Ki(hA2B) = 2 nM; Ki(hA1) = 403 nM; Ki(hA2A) = 503 nM, and Ki(hA3) =570 nM), several groups have discovered second-generation A2BAR ligands thatare suitable for development. Scientists at CV Therapeutics have discovered theselective, high-affinity A2BAR antagonist 22, a 8-(4-pyrazolyl)-xanthine derivative,(CVT-6883, Ki(hA2B) = 22 nM; Ki(hA1) = 1,940 nM; Ki(hA2A)= 3,280; andKi(hA3)= 1,070 nM). Compound 22 has demonstrated favorable pharmacokinetic(PK) properties (T1/2 = 4 h and F > 35% rat), and it is a functional antagonist at

R.V. Kalla (�)Department of Medicinal Chemistry, CV Therapeutics Inc., 3172 Porter Drive,Palo Alto, CA 94304, [email protected]

99C.N. Wilson and S.J. Mustafa (eds.), Adenosine Receptors in Health and Disease,Handbook of Experimental Pharmacology 193, DOI 10.1007/978-3-540-89615-9c© Springer-Verlag Berlin Heidelberg 2009

Copyright for this contribution stays with the National Institute of Health, NIH

4,

100 R.V. Kalla et al.

the A2BAR (KB = 6 nM). In a mouse model of asthma, compound 22 demonstrateda dose-dependent efficacy supporting the role of the A2BAR in asthma. In twoPhase I clinical trails, 22 (CVT-6883) was found to be safe, well tolerated, andsuitable for once-daily dosing. Baraldi et al. have independently discovered a selec-tive, high-affinity A2BAR antagonist, 30 (MRE2029F20), 8-(5-pyrazolyl)-xanthine(Ki(hA2B) = 5.5 nM;Ki(hA1) = 200 nM;Ki(hA2A, A3)> 1,000), that has beenselected for development in conjunction with King Pharmaceuticals. Compound30 has been demonstrated to be a functional antagonist of the A2BAR, and ithas been radiolabeled for use in pharmacological studies. A third compound, 58(LAS-38096), is a 2-aminopyrimidine derivative (discovered by the Almirall group)that has high A2BAR affinity and selectivity (Ki(hA2B)= 17 nM; Ki(hA1)>

1,000 nM; Ki(hA2A)> 2,500; and Ki(hA3)> 1,000 nM), and 58 has been movedinto preclinical safety testing. A fourth selective, high-affinity A2BAR antagonist,54 (OSIP339391 Ki(hA2B)= 0.5 nM; Ki(hA1)= 37 nM; Ki(hA2A)= 328; andKi(hA3)= 450 nM) was discovered by the OSI group. The three highly selective,high-affinity A2BAR antagonists that have been selected for development shouldprove useful in subsequent clinical trials that will establish the role of the A2BARsin various disease states.

Keywords Adenosine receptor antagonist · Asthma · CVT-6883 · MRE2029F20 ·LAS-38096

Abbreviations

AR Adenosine receptorBALF Bronchoalveolar lavage fluidBSMCs Bronchial smooth muscle cellscAMP Cyclic adenosine monophosphateCGS-21680 2-[p-(2-Carboxyethyl)phenylethylamino]-5′-N -

ethylcarboxamidoad enosineCPA N6-CyclopentyladenosineDAG DiacylglycerolHBECs Human bronchial epithelial cellsHRECs Human retinal endothelial cellsIL InterleukinIP3 (1,4,5)Inositol triphosphateMCP-1 Monocyte chemotactic protein-1NECA 5′-N -EthylcarboxamidoadenosineNIDDM Noninsulin-dependent diabetesmellitusNSAIDs Nonsteroidal antiinflammatory drugsPK PharmacokineticSAR Structure–activity relationshipVEGF Vascular endothelial growth factor

Recent Developments in A2B Adenosine Receptor Ligands 101

1 Introduction

The A2B adenosine receptor (AR) is a member of the P1 family of seven-transmembrane ARs, and it couples to Gs to increase cAMP and Gq11 to increase(1,4,5)inositol triphosphate (IP3)/diacylglycerol (DAG) (Fozard and McCarth2002). The A2BAR has been found to be located in smooth muscle cells of thevascular, intestinal, and bronchial tissue, chromaffin tissue, mast cells, and thebrain. The goal of this review is to highlight the structure–affinity relationships(SAR) of A2BAR antagonists that started with early lead compounds with nonopti-mized pharmaceutical properties, which served as the genesis for second-generationcompounds with high selectivity and affinity that have become development can-didates. We will only briefly mention the major indications to demonstrate thepotential utility of A2BAR antagonists, since the potential indications of A2BARhave been described in detail elsewhere (Feoktistov et al. 1998; Holgate ST 2005;Kurukulasuriya et al. 2003; Harada et al. 2001a; Hayallah et al. 2002). Althoughthe A2BAR antagonists described in this review are currently under investigationin order to fully define the role of the A2BAR in disease states, early in vitro andin vivo experiments suggest that A2BAR antagonists may be beneficial for the fol-lowing diseases: asthma—A2BAR mediates inflammatory cytokine release (HolgateST 2005; Zhong et al. 2004, 2005, 2006); diabetes—A2BAR mediates gluconeo-genesis (Harada et al. 2001a, b; Kurukulasuriya et al. 2003); diabetic retinopathy(Feoktistov et al. 2004) and cancer (Zeng et al. 2003)—A2BAR mediates angiogen-esis (Belardinelli and Grant 2001; Feoktistov et al. 2004).

A number of studies have suggested that activation of the A2BAR may playan important role in asthma. Activation of A2BARs on human bronchial smoothmuscle cells (BSMCs) has been shown to induce the release of the inflammatorycytokines interleukin (IL)-6 and monocytic chemotactic protein-1 (MCP-1) (Zhonget al. 2004), on human lung fibroblasts the release of IL-6 and differentiation offibroblasts into myofibroblasts (Zhong et al. 2005), and on human bronchial epithe-lial cells (HBECs) the release of IL-19, which in turn activates human monocytesto induce the release of TNF-α, which in turn upregulates A2BAR expression onHBECs (Zhong et al. 2006). Adenosine levels are elevated in the bronchoalveolarlavage fluid (BALF) of asthmatics relative to healthy volunteers (Driver et al. 1993).Moreover, when AMP is administered to asthmatics and healthy normal individu-als, it provides a source of adenosine that leads to bronchoconstriction in asthmaticsbut not normals (Cushley et al. 1984). Furthermore, an adenosine uptake blocker,dipyridamole, can precipitate asthma (Fozard and McCarth 2002). Therefore, theabove evidence supports the notion that adenosine plays a role in asthma, and thatits effects may be, at least in part, mediated through the A2BAR. For more infor-mation on the role of A2BARs in asthma, the reader is referred to Chap. 11 of thisvolume, “Adenosine Receptors and Asthma” (Wilson et al.).

Scientists at Eisai have provided evidence that the A2BAR antagonists and/ormixed A2B/A1AR antagonists may be useful in the treatment of diabetes. First,they demonstrated that the adenosine agonist analogs NECA [5′-N -ethylcarboxami-doadenosine] (nonselective), CPA [N6-cyclopentyladenosine] (A1-selective) and


CGS-21680 [2-[p-(2-carboxyethyl)phenylethylamino]-5′-N -ethylcarboxamidoade-nosine] (A2A-selective) stimulate glucose production from rat hepatocytes, withNECA having the most pronounced effect (Harada et al. 2001a). Then, the Eisairesearchers found that their high-affinity A2BAR antagonists that possess low se-lectivity over A1AR and A2AAR block NECA-induced glucose production in rathepatocytes. Eisai found in a separate study that the inhibition of glucose productionwas best correlated with the A2BAR affinity of the compounds used in a diabetesmodel (Harada et al. 2001b). Specifically, a nonselective high-affinity A2BAR an-tagonist (52) was found to lower plasma glucose following oral dosing (10 and30 mg kg−1 bodyweight) in a mouse model of noninsulin-dependent diabetes melli-tus (NIDDM), KK-Ay mice (Harada et al. 2001b). It is clear from the above studiesthat adenosine likely plays a role in glucose production; however, the studies shouldbe repeated with the highly selective, high-affinity A2BAR antagonists described inthis review.

Angiogenesis plays a major role in diabetic retinopathy and certain cancers. Inproliferative diabetic retinopathy, it has been shown that activation of the A2BARon human retinal endothelial cells (HRECs) leads to new vessel formation that hasuncontrolled growth, resulting in an increase in the permeability of the vasculature(Feoktistov et al. 2004). Support for a role of the A2BAR in angiogenesis in HRECswas demonstrated when NECA caused a concentration-dependent increase in vas-cular endothelial growth factor (VEGF) mRNA in HRECs which was blocked byantisense oligonucleotides for the A2BAR. Moreover, scientists at CV Therapeuticshave suggested that labeled antibodies directed against the A2BAR are potentiallyuseful tools in detecting and possibly preventing the angiogenesis associated withgliomas, colon cancer, and solid tumors (Belardinelli and Grant 2001).

Finally, since the nonspecific AR antagonist caffeine is known to have intrin-sic antinociceptive properties when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) or opiates, Muller and coworkers investigated anddiscovered that A2BAR antagonists possess antinociceptive effects in a hot platetest (Abo-Salem et al. 2004). In the same study, Muller et al. found that an A2BARantagonist was found to synergize with morphine for an enhanced antinociceptiveeffect in the same manner as caffeine.

2 A2B Adenosine Receptor Antagonists

2.1 Xanthine-Based Antagonists

The naturally occurring alkylxanthines theophylline (1) and caffeine (2) are con-sidered classical antagonists for the ARs. They exhibit weak affinity towards theA2BAR, with no selectivity against the other ARs (Jacobson et al. 1999). Sub-stitution of the dipropyl groups at the 1,3-methyl position of theophylline, as in1,3-dipropyl xanthine, resulted in a 15-fold enhancement of A2BAR affinity. The


introduction of hydrophobic substitution at the 8 position of the xanthine coreincreases affinity towards the ARs. For example, 8-cyclopentyl-1,3-dipropyl xan-thine (3, DPCPX), a known A1AR antagonist, displays good affinity for bothA1 (Ki = 0.9 nM) and A2B (Ki = 56 nM)ARs. Introduction of aryl substitution atthe 8 position of theophylline, as in 1,3-dimethyl-8-phenyl xanthine (4), led to goodaffinity for the A2BAR (Ki = 415 nM), which is a 22-fold enhancement in affin-ity compared to theophylline. Further substitution of uncharged electron-donatinggroups like a methoxy group (5) or a hydroxyl group (6) at the para position of the8-phenyl group enhances the A2BAR affinity. The replacement of the 1,3-methylgroups of 4 with n-propyl groups, as in 7, increased the A2BAR affinity (Jacobsonet al. 1999).

In an effort to develop potent and selective adenosine receptor antagonists,Jacobson et al. selected the 1,3-dipropyl-8-(p-hydoxyphenyl) xanthine as a leadcompound to explore the effect of functionalized congeners (Kim et al. 1999).Initially, the effects of carboxylic acids, amine derivatives and amino acid conju-gates at the para position of the phenyl group were explored, and it was observedthat there was no clear preference for these groups with respect to the A2BARaffinity. The neutral biotin conjugates of various chain lengths were considerablyless potent than the parent amine, whereas the L-thienyl alanine derivative dis-played good affinity (Ki = 6.9 nM) at human A2BAR. The high-affinity compoundsobserved in the series of 8-phenylxanthine functionalized congeners were XCC [8-{4-[(carboxymethyl)oxy]phenyl}-1,3-dipropylxanthine, 8], its hydrazide derivative(9), and another substituted amide derivative (10) (Jacobson et al. 1999) (Table 1).

The hydrazide was reacted with various mono- and dicarboxylic acids, andthis structural change further enhanced selectivity, as exemplified by the dimethyl-malamide derivative (11, MRS1595). Further exploration of the amide derivatives

Table 1 A1, A2A, A2B and A3AR binding affinities of xanthine derivatives at human A2BARsexpressed in HEK-293 cells

N

N N

HN

O

O

O

O

R

Compound R hKi nM A2B SelectivityA2B A1 A2A A3 A1/A2B A2A/A2B A3/A2B

8 OH 13 58 2,200 – 4 169 –9 NHNH2 14 323 21 217 23 1 1610 −NC(O)CH2CH2C(O)− 10 153 127 227 15 13 2311 (MRS1595) NHNdimethylmaloyl 27 3,030 1,970 670 110 74 2512 NH−Ph(4-CF3) 2.14 61 238 213 29 110 10013 (MRS1706) NH−Ph(4-COCH3) 1.4 157 112 230 110 81 17014 NH−Ph(4-I) 2 293 5,140 1,270 140 2,400 60015 (MRS1754) NH−Ph(4-CN) 1.97 403 503 570 205 255 290


Fig. 1 1,3,7,8-Substituted xanthines

by condensing the carboxylic acid group of 8 with substituted phenylamines led tothe discovery of several high-affinity and selective compounds. The anilides sub-stituted at the para position with an electron-withdrawing group (12) showed goodaffinity and selectivity. Also, the para-acetophenone analog 13 displayed good affin-ity and selectivity. The para-halogen-substituted derivatives exhibited high affinityfor the A2BAR, with the para-iodo derivative (14) demonstrating the highest se-lectivity compared to the other halo derivatives (Kim et al. 2000). The para-cyanoanilide derivative (15, MRS 1754) displayed high affinity for the A2BAR (Ki =1.97 nM) and 205-, 255-, and 290-fold selectivity versus human A1/A2A/A3ARs,respectively (Kim et al. 2002) (Table 1).

The 1-alkyl-8-phenyl(cyclopentyl) xanthine derivatives were found to exhibithigh affinity for A2BARs (Hayallah et al. 2002). In this study, the 1,8-disubstitutedxanthine derivatives were shown to be equipotent to or more potent than 1,3,8-trisubstituted xanthines at A2BARs, but generally less potent at A1 and A2A,and much less potent at A3AR subtypes. 1-Propyl-8-p-sulfophenylxanthine(16, PSB1115) was the most selective compound of this family, exhibiting a Kivalue of 53 nM at human A2BAR. This compound is highly water soluble dueto its sulfonate functional group. The 4-nitrophenylester of PSB1115 is also re-ported to be a potential prodrug despite its significant binding affinity for theA1AR subtype (rA2B = 5.4 nM, rA1 = 3.6 nM) (Hayallah et al. 2002). 1-Butyl-8-p-carboxyphenylxanthine (17), another polar analog bearing a carboxylate functionalgroup, exhibited a Ki value of 24 nM for A2BARs, 49-fold selectivity versus humanand 20-fold selectivity versus rat A1AR subtype, and greater than 150-fold selectiv-ity versus human A2A and A3ARs (Yan and Muller 2004) (Fig. 2).


Fig. 2 1,8-Substituted xanthines

Fig. 3 8-(Pyrazol-4-yl)xanthines as A2BAR antagonists

Chemists at CV Therapeutics have explored various heterocycles as bioisostericreplacements for the 8-phenyl group of 1,3-dipropyl-8-phenyl xanthines, and theyobserved that 1,3-dipropyl-8-(4-pyrazolyl)xanthine 18 displayed a high affinity forthe A2BAR (Kalla et al. 2004). Substitution of the N-1 pyrazole with a benzyl group,as in 19, retained the A2BAR affinity compared to the phenethyl and phenpropylgroups (Fig. 3). Further substitution of the phenyl ring with electron-withdrawinggroups, for example CF3 at the meta-position (20), increased the A2BAR selec-tivity. Replacing the 1,3-dipropyl groups of the xanthine core with 1,3-dimethylgroups resulted in 21, which has both high affinity and selectivity for the A2BAR(Kalla et al. 2006). Exploration of differential substitution at the N-1 and N-3positions of the xanthine core led to compound 22 (CVT-6883), which has goodaffinity for the A2BAR and displayed good selectivity (Elzein et al. 2008). Theintroduction of monosubstitution at the N-1 position of the xanthine core, as incompound 23, enhanced the selectivity compared to the disubstituted derivative 20(Kalla et al. 2008). The N-3 monosubstituted derivative 24 lost the A2BAR affin-ity, and this is in agreement with Hayallah et al.’s observation for the 8-phenylseries that 1,8-disubstituted xanthine derivatives display better A2BAR affinities andselectivities than the 3,8-disubstituted xanthine derivatives (Hayallah et al. 2002).Replacing the phenyl group of 20 with different heterocycles, including 3-phenyl-


1,2,4-oxadiazoles, 5-phenyl-1,2,4-oxadiazoles and 3-phenyl-isoxazoles, resulted incompounds that display high affinity and good selectivity regardless of the substi-tution at the N-1 and N-3 positions on the xanthine core (25 and 26) (Elzein et al.2006). The N-1 monosubstituted oxadiazole 27 and isoxazole 28 displayed highaffinity and selectivity for the A2BAR (Kalla et al. 2008). Compound 22 (6883)antagonized the NECA-induced cAMP accumulation in HEK-A2B cells and NIH3T3 cells (Sun et al. 2006), and compound 26 (6694) completely abolished theNECA-induced cAMP accumulation in BSMCs (Zhong et al. 2004), confirmingthat these compounds are antagonists for the hA2BAR. In a mouse model of asthma,compound 22 demonstrated a dose-dependent blocking effect on NECA-inducedincreases in airway reactivity (Mustafa et al. 2007). Also, in this mouse model ofallergic asthma, compound 22 significantly reduced the late allergic airway responseand inflammatory cells in BALF, supporting the role of the A2BARs in asthma(Table 2).

Several heterocycles, such as pyrazole, isoxazole, pyridine and pyridazine, linkedby different spacers (substituted acetamido, oxyacetamido and urea moieties)at the 8 position of the xanthine nucleus were investigated (Baraldi et al.2004a). The synthesized compounds showed A2BAR affinities in the nanomolarrange and good levels of selectivity, as evaluated in radioligand binding as-says at human A1, A2A, A2B, and A3ARs. This study allowed the identificationof the derivatives 2-(3,4-dimethoxy-phenyl)-N -[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H -purin-8-yl)-1-methyl-1H -pyrazol-3-yl]-acetamide (29, MRE2028-F20) [Ki(hA2B)= 38 nM, Ki (hA1, hA2A, hA3)> 1,000 nM], N -benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H -purin-8-yl)-1-methyl-1H -pyrazol-3-yloxy]-acetamide (30, MRE2029F20) [Ki (hA2B)= 5.5 nM,

Ki (hA1)= 200 nM, (hA2A, hA3)> 1,000], and N -(3,4-dimethoxy-phenyl)-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H -purin-8-yl)-1-methyl-1H -pyrazol-3-yloxy]acetamide (31, MRE2030F20) [Ki (hA2B = 12 nM, Ki (hA1, hA2A, hA3)

> 1,000 nM] (Fig. 4), which showed high affinity at the A2BAR subtype and verygood selectivity versus the other AR subtypes. The derivatives with higher affinityat human A2BAR proved to be antagonists in the cyclic AMP assay, capable of in-hibiting the stimulatory effect of NECA (100 nM) with IC50 values in the nanomolarrange and a trend similar to that observed in the binding assay.

Compounds 32, 33 (Fig. 4) bearing the isoxazole nucleus at the 8 position showedlower affinities at the A2BAR than the corresponding 8-pyrazole derivatives. How-ever, replacing the pyrazole ring with an isoxazole enhanced selectivity versus theA1AR. Consequently, the radiolabeled analog of compound N -benzo[1,3]dioxol-5-yl-2-[5-(1,3-diallyl-2,6-dioxo-2,3,6,7- tetrahydro-1H -purin-8-yl)-1-methyl-1H -pyrazol-3-yloxy]-acetamide (30) was prepared in the tritium-labeled form [3H]MRE2029F20, which displayed a Kd value of 1.65 ± 0.10 nM). This compoundwas found to be a selective, high-affinity radioligand that is useful for char-acterizing recombinant human A2BARs (Baraldi et al. 2004b). Very recently,the same authors also described a series of 1,3-dipropyl-8-(1-phenylacetamide-1H -pyrazol-3-yl)-xanthines as selective A2BAR antagonists (Aghazadeh Tabriziet al. 2008). The 4-chlorophenyl derivative 34 (Fig. 4) was found to be the most


Tabl

e2

A1,

A2A

,A

2Ban

dA

3AR

bind

ing

affin

ities

of8-

(4-p

yraz

olyl

)xan

thin

ean

alog

s

N

NNH N

NN

O

OR1

R3

R

N

NNH N

NN

O

OR1

NOX

R

R3

20-2

425

-28

Com

poun

dR

1R

3R

hKi

nMA

2BSe

lect

ivity

A2B

A1

A2A

A3

A1/

A2B

A2A

/A

2BA

3/A

2B

20Pr

opyl

Prop

ylC

F 314

160

400

140

1227

1021

Met

hyl

Met

hyl

CF 3

199

069

01,

000

990

690

1,00

022

(CV

T-68

83)

Prop

ylE

thyl

CF 3

221,

940

3,28

01,

070

8814

948

23Pr

opyl

HC

F 38

>6,

000

>5,

000

700

>75

0>

620

8024

HPr

opyl

H>

6,00

0nd

ndnd

ndnd

nd25

(X=

N)

Prop

ylPr

opyl

CF 3

21>

6,00

0>

5,00

01,

300

>29

0>

240

6026

(X=

N)

(CV

T-66

94)

Prop

ylH

Cl

7>

6,00

0>

5,00

0>

9,00

0>

850

>70

0>

1,28

0

27(X

=N

)C

yclo

prop

ylm

ethy

lH

CF 3

13>

6,00

0>

5,00

0>

9,00

0>

460

>38

0>

700

28(X

=C

)C

yclo

prop

ylm

ethy

lH

CF 3

15>

6,00

0>

5,00

0>

9,00

0>

400

>33

3>

600


Fig. 4 1,3,8-Substituted xanthines

Fig. 5 Substituted 8-pyridyl xanthines as A2BAR antagonists

potent (KiA2B = 7.0 nM) and selective compound within the series (A1, A2A, A3/

A2B > 140).Scientists at Adenosine Therapeutics describe a series of 8-(3-pyridyl)xanthines

that have high affinity for the A2BAR. The morpholino derivative 35 and the pyra-zolyl derivative 36 possess better than 100 nM affinity for the A2BAR based uponthe published patent application (Wang et al. 2006). The compounds demonstratethat the six-membered pyridyl ring can serve as a favorable linker, providing highaffinity for the A2BAR in a similar manner to the 4-pyrazolyl and 5-pyrazolyl linkersdescribed above (Fig. 5).


2.2 Deazaxanthine-Based Antagonists

In the xanthine family, the 8-substituted-9-deaza-xanthines are reported to beantagonists with nanomolar affinities for the A2BAR (Carotti et al. 2006;Stefanachi et al. 2008). The 1-, 3-, 8-, and 9-substituted-deazaxanthines of generalstructure 37 (Fig. 6) were prepared and evaluated for their binding affinities atthe recombinant human ARs, in particular at the hA2B and hA2AAR subtypes.1,3-Dimethyl-8-phenoxy-(N -p-halo-phenyl)-acetamido-9-deazaxanthine deriva-tives appeared to be the most interesting leads, with some of them, such as thecompound (N -(4-bromo-phenyl)-2-[4-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H -pyrrolo[3,2-d]pyrimidin-6-yl)-phenoxy]-acetamide (38), showing high hA2BARaffinities and selectivity over hA2A and hA3ARs, but low selectivity over hA1AR.Structure–affinity relationships suggested that the binding potency at the hA2BARwas mainly modulated by the steric (lipophilic) properties of the substituentsat positions 1 and 3 and by the electronic and lipophilic characteristics of thesubstituents at position 8. Electron-withdrawing groups in the para-position of theanilide phenyl ring increased the activity. Regarding the hA2B/hA2AAR selectivity,

Fig. 6 General structures and binding affinities of deazaxanthine derivatives


the most interesting result came from the introduction of a methoxy substituent inthe ortho position of the 8-phenyl ring, which led to an enhancement in selectivityfor compound 39, making it 1,412-fold more selective for the hA2BAR over thehA2AAR.

The 9-deaza analog 40 of the 8-(4-pyrazolyl)xanthine class was synthesizedto compare its A2BAR affinity and selectivity (Kalla et al. 2005). Compound 41,a 9-deaza derivative with a meta-fluoro substitution on the pyrazole ring, has thesame affinity as the direct xanthine analog. Compound 42, a meta-CF3 derivativeand a direct analog of compound 20, displayed a lower affinity for the A2BAR butgood selectivity.

A new series of 4-(1,3-dialkyl-2,4-dioxo-2,3,4,5-tetrahydro-1H -pyrrolo[3, 2-d]pyrimidin-6-yl)benzenesulfonamides (43–46, Table 3) are also reported to bepotent A2BAR antagonists (Esteve et al. 2006). In this series, the 6-(4-{[4-(4-bromobenzyl)piperazin-1-yl]sulfonyl}phenyl)-1,3-dimethyl-1H -pyrrolo[3,2-d]pyrimidine-2,4(3H, 5H)-dione (45) showed a high affinity for the A2BAR (IC50 =1 nM) and selectivity. The presence of metabolically stable benzenesulfonamide inthis novel class of compounds improved their physiochemical properties, resultingin increased oral bioavailability.

Table 3 Deazaxanthine-benzenesulfonamides as A2BAR antagonists

N

N

HN

S

O

O

R1

R O

O

R2

Compound R R1 R2 hA2B hA1 hA3

IC50 (nM)

43 CH3 CH3

HN N

14 150 2,085

44 CH3 CH3N N

16 415 3,169

45 CH3 CH3N N

Br

1 183 12,260

46 nC3H7 CH3N N

CN

6 370 950


2.3 Adenine-Based Antagonists

Adenine has proven to be a useful core for the development of AR antagonists. Mod-ifications of adenine led to various 2- and 8-substituted derivatives with moderateaffinities at all four AR subtypes (Campioni et al. 1998). Generally, it appears that2-substitution led to nonselective antagonists or to antagonists with high affinitiesat both A1 and A2AARs. In the series of 8-bromo-9-alkyl-adenines 47–50 (Table 4),the presence of a propyl group at the 9 position and a bromine at the 8 posi-tion, such as in compound 49 (hA2B Ki = 200 nM), increased the affinity andselectivity for the A2B receptor in comparison to the parent 9-ethyladenine, with aKi value of 0.84 μM. The experimental data show that different substituents in the8 position result in compounds with quite different pharmacological features. The8-phenethylamino, 8-phenethoxy, and 8-(ar)alkynyl compounds generally showedlower potency at all receptors than compound 48. Replacement of the N9 ethyl witha methyl group retained A2BAR affinity and decreased affinity at all other AR sub-types, while the N9 bulky groups led to derivatives with higher selectivity versusA2BAR (Lambertucci et al. 2000; Volpini et al. 2003).

The 2-alkynyl-8-aryl-9-methyladenine derivatives were also synthesized ascandidate hypoglycemic agents (Harada et al. 2001a). These analogs were eval-

Table 4 Adenine derivatives as A2BAR antagonists

N

N N

N

B r

NH2

R R hA2B hA1 hA2A hA3

Ki(nM) Ki(nM)

47 CH3 720 570 120 >100,00048 C2H5 840 280 52 28,00049 C3H7 200 1,100 300 >100,00050 cC5H9 860 1,000 1,900 4,200

N

N N

N

R

NH2

CH3OH

51 O 14 25 11 –

52

F

23 14 16 540


Fig. 7 Deazapurines as A2BAR antagonists

uated for inhibitory activity on N -ethylcarboxamidoadenosine (NECA)-inducedglucose production in primary cultured rat hepatocytes. The introduction ofvarious heteroaromatic rings and (substituted) phenyl rings at the 8 position of9-methyladenine, and of other alkynyl groups at the 2 position, was investigated.The aromatic groups in the 8 position significantly increased the potency, andthe preferred substituents at the 8 position of adenine were the 2-furyl and 3-fluorophenyl groups (51 and 52 respectively, Table 4). Another modification atthe alkynyl side chain, changes in ring size, cleavage of the ring, and removal of thehydroxyl group were all well tolerated. Compound 52 is a nonspecific adenosineantagonist, but it was hypothesized that its inhibition of hepatic glucose productionvia the A2BAR could be at least one of the mechanisms associated with its in vivoactivity.

Scientists at OSI Pharmaceuticals have discovered several very high affinityA2BAR antagonists, 53 and 54 (OSIP339391), that are based on a deaza-adeninescaffold (Castelhano et al. 2003) (Fig. 7). Compound 54 has extremely high affinityfor the A2BAR, making it suitable for use as a radiolabeled ligand for com-petitive binding assays, and it possesses moderate selectivity over hA1, hA2Aand hA3ARs (>70-fold). The tritium-labeled 54 was prepared from the acetyleneprecursor, affording a compound with radiolabeled OSIP339391 that had a selectiv-ity of greater than 70-fold for A2BARs over other human AR subtypes (Stewart et al.2004). The radiolabel was introduced by hydrogenation of the acetylenic precursor,affording a compound with high specific activity. These compounds should possessgood water solubilities, since they incorporate a basic piperidine or piperazine moi-ety that should be protonated at physiological pH. It would be interesting to knowwhether these compounds are metabolically stable and whether they have favorablePK properties, but this information has not been reported.

2.4 2-Aminopyridine-Based Antagonists

2-Aminopyridine derivatives that are selective A2BAR antagonists have been re-ported (Harada et al. 2004). The core structure of this class of compounds is


Table 5 2-Aminopyridine derivatives as A2BAR antagonists

N R2

R1NC

H2N

hA1 hA2AR1 R2 Ki(nM) hA2BIC50 (nM)

55 4-Pyridine 2-Furyl 990 23 2.756 4-Pyridine 3-Fluoro-

phenyl66 22 3.7

57 1-Ethyl-6-oxo-3-pyridine 2-Furyl 400 7 6.5

a 2-aminopyridine that presents a cyano group at the 3 position together withsubstituents at the 4 and 5 positions (55–57). Few data were presented, but ana-log 55 (6-amino-2-(2-furyl)-3,4′-bipyridine-5-carbonitrile; Table 5) showed at leastninefold selectivity and good affinity at A2BAR. Apparently, the introduction of afuryl group at the 2 position and a pyridine group at the 4 position (55) introducedsome selectivity with respect to the A1AR and A2AAR, respectively.

2.5 Bipyrimidine-Based Antagonists

2-Amino-substituted pyrimidines have been identified as suitable templates for theconstruction of adenosine A2BAR antagonists (Vidal et al. 2007c). Several com-pounds of this novel series of N -heteroaryl-4′-(furyl)-4,5′-bipyrimidin-2′-amines(Table 6) were very selective over other ARs and had a low nanomolar affinity atthe A2BAR. The introduction of unsubstituted nitrogen-containing heterocycles inR1, such as pyridine, pyrimidine or pyrazine, yielded compounds 58–67. Amongthese, the 3-pyridyl derivative 58 (LAS-38096) was found to show high potencyand selectivity. Substitution by a methoxy group (61 and 62) led to a drop in po-tency while retaining good selectivity. Compounds 63 and 64 were investigated toevaluate the effect of substitution of the nitrogen atoms of the 3-pyridyl or the 3-pyrimidinyl rings with a hydrogen bond acceptor. The cyano derivative 63 showedlower affinity but an increase in selectivity versus A2AAR. The N -oxide 64 hada twofold decrease in affinity compared to that of the corresponding reduced ana-log 58. The introduction of a pyridone moiety yielded compound 65, which wasfound to be one of the most potent and selective compounds within the series.Alkylation at the pyridine nitrogen had a slightly detrimental effect on A2BARpotency for the more lipophilic analog 67. LAS-38096, which represents the leadfor this series, was capable of inhibiting A2BAR-mediated NECA-dependent in-creases in intracellular cAMP, with IC50 values of 321 nM and 349 nM in cellsexpressing human and mouse ARs, respectively; it also displayed a favorable PKprofile in preclinical species. The efficacy of compound 58 was evaluated in vivoin an allergic mouse model, and the mice showed significantly less bronchial


Table 6 2-Amino substituted pyrimidines as A2BAR antagonists

N N

N

NHN

R1O

hA2B hA2A hA1 hA3

R1 Ki (nM)

58 (LAS-38096) 3-Pyridyl 17 >2, 500 >1, 000 >1, 00059 3-Pyrimidinyl 24 >2, 500 >10, 000 >1, 00060 2-Pyrazinyl 116 >2, 500 >10, 000 >1, 00061 6-Methoxypyridin-3-yl 115 >2, 500 >10, 000 >1, 00062 2-Methoxypyrimidin-5-yl 39 >2, 500 >10, 000 >1, 00063 5-Cyano-pyridin-3-yl 69 >2, 500 >10, 000 >1, 00064 1-Oxido-pyridin-3-yl 34 >2, 500 >10, 000 >1, 00065 6-Oxo-1,6-dihydropyridin-3-yl 16 >2, 500 >10, 000 >1, 00066 1-Methyl-6-oxo-1,6-

dihydropyridin-3-yl28 >2, 500 >10, 000 >1, 000

67 1-Cyanopropylmethyl-6-oxo-1,6- dihydropyridin-3-yl

119 >2, 500 >10, 000 >1, 000

hyperresponsiveness, mucus production, and a slight decrease in eosinophil infil-tration and Th2 cytokine levels (Aparici et al. 2006).

2.6 Pyrimidone-Based Antagonists

A series of compounds with a pyrimidine-4-(3H)-one core structure has been re-ported as antagonists for the A2BAR (Harada et al. 2003). However, few data werereported, and data on the A3AR are lacking. The most representative compound,2-amino-6-(2-furyl)-3-methyl-5-(4-pyridyl)pyrimidin-4-(3H)-one (69), derived byintroducing a methyl group at the 3 position of the unsubstituted analog 68, gaveKi values of 966 nM and 493 nM, respectively, against A1 and A2AARs in bind-ing assays. It also inhibited NECA-stimulated cAMP production in A2B-transfectedCHO-K1 cells, with an IC50 value of 71 nM (Table 7).

2.7 Imidazopyridine-Based Antagonists

The imidazopyridine nucleus was recently identified in a patent as a core structurein a new series of A2BAR antagonists (Vidal et al. 2005). This patent presented fewdata, and data on the A1, A2A and A3ARs are lacking. Several compounds (70–75)of this new class had low nanomolar (<10 nM) affinities for the A2BAR (Table 8).


Table 7 Pyrimidone derivatives as A2BAR antagonists

N

N

O

NO

NH2

R hA1 hA2AR hA2BIC50(nM) Ki(nM)

68 H 256 1108 34569 CH3 71 966 493

Table 8 Imidazopyridines as A2BAR antagonists

N NH

N

N

NF

R

R1

R2

R R1 R2 hA2BKi(nM)

70 OCH3 H H 0.871 N(CH3)2 H H 1.772 COOH H H 873 CH3 F H 2.274 H F H 2.875 F H F 2.8

2.8 Pyrazine-Based Antagonists

Scientists at Almirall Pharmaceuticals have found that pyrazine derivatives arenovel potent antagonists of A2BARs (Vidal et al. 2007a, b). Table 9 shows thebinding activities for human A2BAR of some of these compounds (76–83). Inthis patent, affinity data for other AR subtypes are lacking. Generally, these 2-aminopyrazines present the pyridine nucleus at the 5 and 6 positions. Apparently,the introduction of a furyl group at the 6 position of the pyrazine ring (79) was toler-ated by A2BARs. The imidazopyrazine 80 also showed high affinity at A2BAR. Thelead compound of this new series is 2-(3-fluoropyridin-4-yl)-3,6-di(3-pyridyl)-5H -pyrrolo[2,3-b]pyrazine, 83 (Ki = 0.9 nM).


Tabl

e9

Pyra

zine

deriv

ativ

esas

A2B

AR

anta

goni

sts

Com

poun

dC

hem

ical

stru

ctur

ehA

2BK

i(n

M)

Com

poun

dC

hem

ical

stru

ctur

ehA

2BK

i(n

M)

76

NNN

H2

N

F

Cl

480

NN

N

F

N HH N

O

4

77

NNH N

N

N

Cl

O

1681

NNH N

NF

O

N

F

3


78

NNH N

N

N

F

O

1982

NNH N

N

N

F

O

H3C

O

26

79

NH

2

NN

N

OC

H3

O

983

NN

N

N

F

H NN

0.9


2.9 Pyrazolo-Triazolo-Pyrimidine-Based Antagonists

Pyrazolo[4,3-e]1,2,4-triazolo-[1,5-c]pyrimidine derivatives were initially investi-gated for the development of selective A3AR antagonists (Baraldi et al. 2000,2002). From preliminary studies, it has been demonstrated that the N5-unsubstitutedderivatives show different binding profiles according to the substitution position (N7or N8) on the pyrazole nucleus. The N7 derivatives showed high affinity for the hu-man A2AARs but did not bind to the human A2BAR subtype (range > 1 μM). TheN8-substituted derivatives (derivatives with phenethyl or iso-pentyl groups, such asin compounds 84 and 85, Table 10) displayed affinity in the nanomolar range to hu-man A2BAR, but no selectivity versus the A1 and A2AAR subtypes was observed. Inparallel studies on human A3AR antagonists, it was observed that the introductionof a phenylacetyl group at the N5 position (86) produces an increase in affinity atthe A3AR. In fact, a combination of an aryl acetyl moiety at the N5 position and aphenylethyl or phenylpropyl group at the N8 position led to compounds 87 and 88,which were found to be nonselective AR antagonists. The introduction of an alkyl-carbamoyl moiety at the N5 position yielded 89, which is also a nonselective ARantagonist (Baraldi et al. 2001). The introduction of a α-naphthoyl chain at the N5position instead of a phenyl group (90) was tolerated by the A2BAR but not theother AR subtypes, resulting in the most selective A2BAR antagonist of this series(Pastorin et al. 2003).

Table 10 Pyrazolo[4,3-e]1,2,4-triazolo-[1,5-c]pyrimidines as A2BAR antagonists

N N

N

N

N

N O

H NR

R1 hA1 hA2B hA2A hA3R R1 Ki(nM)

84 H (CH2)2Ph 1 5 0.31 2, 03085 H Iso-pentyl 2 9 0.8 70086 COCH2Ph Methyl 702 165 423 0.8187 COCH2Ph (CH2)2Ph 120 35 60 4588 COCH2Ph (CH2)3Ph 75 40 60 12189 CO(CH2)3NH3 (CH2)2Ph 1.6 27 54 6590 α-Naphthoyl (CH2)3Ph 1, 100 20 800 300


3 Conclusion

The challenge to obtain second-generation, selective, high-affinity A2BARantagonists has been met, as exemplified by the xanthines 8-(4-(N -1-benzyl-pyrazolyl))xanthine 22 (A2BAR Ki = 1 nM, CV Therapeutics) and 8-(5-pyrazolyl)xanthine 30 (A2BAR Ki = 5.5 nM, Baraldi et al. and King Pharmaceuticals) and thepyrimidine 2-(amino-5-pyrimidinyl)pyrimidine 58 (A2BAR Ki = 17 nM, AlmiralProdesfarma). These compounds should prove useful as tools to define the roleof the A2BAR in various disease states, including asthma, diabetes, cancer, andmanagement of inflammatory pain in clinical trials in the near future.

References

Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A, Filipek B, Zimmer A, Muller CE (2004)Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther308:358–366

Aghazadeh Tabrizi M, Baraldi PG, Preti D, Romagnoli R, Saponaro G, Baraldi S, MoormanAllan R, Zaid AN, Varani, Borea PA (2008) 1,3-Dipropyl-8-(1-phenylacetamide-1H -pyrazol-3-yl)-xanthine derivatives as highly potent and selective human A2B adenosine receptorantagonists. Bioorg Med Chem 16:2419–2430

Aparici M, Nueda A, Beleta J, Prats N, Fernandez R, Miralpeix M (2006) A potent adenosineA2B receptor antagonist attenuates methacholine-induced bronchial hyperresponsiveness, mu-cus production and IgE levels in an allergic mouse model (Poster 162). In: CIA Symp, Malta,5–10 May 2006

Baraldi PG, Cacciari B, Romagnoli R, Merighi S, Varani K, Borea PA, Spalluto G (2000) A3adenosine receptor ligands: history and perspectives. Med Res Rev 20:103–128

Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Varani K, Gessi S, Merighi S, Borea PA (2001)Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: a new pharmacological tool for thecharacterization of the human A3 adenosine receptor. Drug Dev Res 52:406–415

Baraldi PG, Cacciari B, Moro S, Spalluto G, Pastorin G, Da Ros T, Klotz KN, Varani K, Gessi S,Borea PA (2002) Synthesis, biological activity, and molecular modeling investigation of newpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A3 adenosine receptorantagonists. J Med Chem 45:770–780

Baraldi PG, Aghazadeh Tabrizi M, Preti D, Bovero A, Romagnoli R, Fruttarolo F, Zaid AN, Moor-man Allan R, Varani K, Gessi S, Merighi S, Borea PA (2004a) Design, synthesis, and biologicalevaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2Badenosine receptor antagonists. J Med Chem 47: 1434–1447

Baraldi PG, Aghazadeh Tabrizi M, Preti D, Bovero A, Romagnoli R, Fruttarolo F, MoormanAllan R, Varani K, Borea PA (2004b) [3H]-MRE 2029-F20, a selective antagonist radioligandfor the human A2B adenosine receptors. Bioorg Med Chem Lett 14:3607–3610

Belardinelli L, Grant MB (2001) Method for identifying and using A2B adenosine receptor antag-onists to mediate mammalian cell proliferation. WO Patent 01060350

Campioni E, Costanzi S, Vittori S, Volpini R, Klotz KN, Cristalli G (1998) New substituted9-alkylpurines as adenosine receptor ligands. Bioorg Med Chem 6:523–533

Carotti A, Cadavid MI, Centeno NB, Esteve C, Loza MI, Martinez A, Nieto R, Ravina E, SanzF, Segarra V, Sotelo E, Stefanachi A, Vidal B (2006) Design, synthesis, and structure–activityrelationships of 1-,3-,8-, and 9-substituted-9-deazaxanthines at the human A2B adenosine re-ceptor. J Med Chem 49:282–299


Castelhano AL, McKibben B, Steinig AG (2003) Pyrrololopyrimidine A2B selective antagonistcompound, their synthesis and use. WO Patent 2003053361

Cushley MJ, Tattersfield AE, Holgate ST (1984) Adenosine-induced bronchoconstriction inasthma: antagonism by inhaled theophylline. Am Rev Respir Dis 129:380–384

Driver AG, Kukoly CA, Ali S, Mustafa SJ (1993) Adenosine in bronchoalveolar lavage fluid inasthma. Am Rev Respir Dis 148:91–97

Elzein E, Kalla R, Li X, Perry T, Parkhill E, Palle V, Varkhedkar V, Gimbel A, Zeng D,Lustig D, Leung K, Zablocki J (2006) Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H -pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists.Bioorg Med Chem Lett 16:302–306

Elzein E, Kalla RV, Li X, Perry T, Gimbel A, Zeng D, Lustig D, Leung K, Zablocki J (2008)Discovery of a novel A2B adenosine receptor antagonist as a clinical candidate for chronicinflammatory airway diseases. J Med Chem 51:2267–2278

Esteve C, Nueda A, Dıaz JL, Beleta J, Cardenas A, Lozoya E, Cadavid MI, Loza MI, Ryder H,Vidal B (2006) New pyrrolopyrimidin-6-yl benzenesulfonamides: potent A2B adenosine recep-tor antagonists. Bioorg Med Chem Lett 16:3642–3645

Feoktistov I, Wells JN, Biaggioni I (1998) Adenosine A2B receptors as therapeutic targets. DrugDev Res 45:198–206

Feoktistov I, Ryzhov S, Zhong H, Goldstein AE, Matafonov A, Zeng D, Biaggioni I (2004)Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells towardan A2B angiogenic phenotype. Hypertension 44:649–654

Fozard JR, McCarth C (2002) Adenosine receptor ligands as potential therapeutics in asthma. CurrOpin Investig Drugs 3:69–77

Fredholm BB, IJzerman AP, Jacobson KA, Kloz K-N, Linden J (2001) International Union ofPharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev53:527–552

Harada H, Asano O, Hoshino Y, Yoshikawa S, Matsukura M, Kabasawa Y, Niijima J, Kotake Y,Watanabe N, Kawata T, Inoue T, Horizoe T, Yasuda N, Minami H, Nagata K, Murakami M,Nagaoka J, Kobayashi S, Tanaka I, Abe S (2001a) 2-Alkynyl-8-aryl-9-methyladenines as noveladenosine receptor antagonists: Their synthesis and structure-activity relationships toward hep-atic glucose production induced via agonism of the A2B receptor. J Med Chem 44:170–179

Harada H, Asano O, Kawata T, Inoue T, Horizoe T, Yasuda N, Nagata K, Murakami M, Nagaoka J,Kobayashi S, Tanaka I, Abe S (2001b) 2-Alkynyl-8-aryladenines possessing an amide moiety:their synthesis and structure-activity relationships of effects on hepatic glucose production in-duced via agonism of the A2B adesnosine receptor. Bioorg Med Chem 9:2709–2726

Harada H, Asano O, Miyazawa S, Yasuda N, Kabasawa Y, Ueda M, Yasuda M, Kotake Y(2003) Pyrimidone compounds and pharmaceutical compositions containing the same. WO2003035640

Harada H, Asano O, Yasuda N, Ueda M. Yasuda M, Miyazawa S (2004) 2-Aminopyridine com-pounds and thereof as drugs. US Patent 6750232

Hayallah AM, Sandoval-Ramırez JS, Reith U, Schobert U, Preiss B, Schumacher B, Daly JW,Muller CE (2002) 1,8-Disubstituted xanthine derivatives: synthesis of potent A2B-selectiveadenosine receptor antagonists. J Med Chem 45:1500–1510

Holgate ST (2005) The Quintiles Prize Lecture 2004: the identification of the adenosine A2B re-ceptor as a novel therapeutic target in asthma. Br J Pharmacol 145:1009–1015

Jacobson KA, IJzerman AP, Linden J (1999) 1,3-Dialkylxanthie derivatives having high potencyas antagonists at human A2B adenosine receptors. Drug Dev Res 47:45–53

Kalla R, Perry T, Elzein E, Varkhedkar V, Li X, Ibrahim P, Palle V, Xiao D, Zablocki J (2004) A2Badenosine receptor antagonists. US Patent 6,825,349

Kalla R, Elzein E, Marquart T, Perry T, Li X, Zablocki J (2005) A2B adenosine receptor antagonists.WO Patent 2005042534

Kalla R, Elzein E, Perry T, Li X, Palle V, Varkhedkar V, Gimbel A, Maa T, Zeng D, Zablocki J(2006) Novel 1,3-disubstituted 8-(1-benzyl-1H -pyrazol-4-yl)xanthines: High affinity and se-lective A2B sdenosine receptor antagonists. J Med Chem 49:3682–3692


Kalla R, Elzein E, Perry T, Li X, Gimbel A, Yang M, Zeng D, Zablocki J (2008) Selective, highaffinity A2B adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines.Bioorg Med Chem Lett 18:1397–1401

Kim Y-C, Karton Y, Ji X-D, Melman N, Linden J, Jacobson KA (1999) Acyl hydrazide derivativesof a xanthine carboxylic congener (XCC) as selective antagonists at human A2B adenosinereceptor. Drug Dev Res 47:178–188

Kim Y-C, Ji X-D, Melman N, Linden J, Jacobson KA (2000) Anilide derivatives of a8-phenylxanthine carboxylic congener are highly potent and selective antagonists at humanA2B adenosine receptors. J Med Chem 43:1165–1172

Kim S-A, Marshall MA, Melman N, Kim HS, Muller CE, Linden J, Jacobson KA (2002)Structure–activity relationships at human and rat A2B adenosine receptors of xanthine deriva-tives substituted at the 1-, 3-, 7-, and 8-positions. J Med Chem 45:2131–2138

Kurukulasuriya R, Link JT, Madar DJ, Pei Z, Richards SJ, Rhode JJ, Souers AJ, Szczepakieicz BG(2003) Potential drug targets and progress towards pharmacologic inhibition of hepatic glucoseproduction. Curr Med Chem 10:123–153

Lambertucci C, Campioni E, Costanzi G, Kachler S, Klotz KN, Volpini R, Cristalli G, Vittori S(2000) A bromine atom in C-8 position of 9-substituted adenines enhnces A2A. Drug Dev Res50:67–74

Mustafa SJ, Nadeem A, Fan M, Zhong H, Belardinelli, Zeng D (2007) Effect of a specific andselective A2B adenosine receptor antagonist on adenosine agonist AMP and allergen-inducedairway responsiveness and cellular influx in a mouse model of asthma. J Pharmacol Exp Ther320:1246–1251

Pastorin G, Da Ros T, Spalluto G, Deflorian F, Moro S, Cacciari B, Baraldi PG, Gessi S, Varani K,Borea PA (2003) Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine re-ceptor antagonists. Influence of the N5 substituent on the affinity at the human A3 and A2Badenosine receptor subtypes: a molecular modelling investigation. J Med Chem 46:4287–4296

Stefanachi A, Nicolotti O, Leonetti F, Cellamare S, Campagna F, Loza MI, Brea JM,Mazza F, Gavuzzo E and Carotti A (2008) 1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthinesas potent A2B adenosine receptor antagonists: design, synthesis, structure–affinity andstructure–selectivity relationships. Bioorg Med Chem 16:9780–9789

Stewart M, Steinig AG, Ma C, Song J-P, McKibben B, Castelhano AL, MacLennan SJ (2004)[3H]OSIP339391, a selective, novel, and high affinity antagonist radioligand for adenosine A2Breceptors. Biochem Pharmacol 68:305–312

Sun C-X, Zhong H, Mohsenin A, Morschi E, Chunn JL, Molina JG, Belardinelli L, Zeng D,Blackburn M (2006) Role of A2B adenosine receptor signaling in adenosine-dependent pul-monary inflammation and injury. J Clin Invest 116:2173–2182

Vidal JB, Esteve TC (2005) Pyrimidin-2-amine derivates and their use as A2B adenosine receptorantagonists. WO Patent 2005040155

Vidal JB, Esteve TC, Soca PL, Eastwood PR (2007a) Pyrazine derivatives useful as adenosinereceptor antagonists. WO Patent 2007017096

Vidal JB, Fonquerna PS, Eastwood PR, Aiguade BJ, Cardus FA, Carranco MI, Gonzalez RJ,Paredes AS (2007b) Imidazopyridine derivatives as A2B adenosine receptor antagonists. WOPatent 2007039297

Vidal JB, NA, Esteve TC, Domenech T, Benito S, Reinoso RF, Pont M, Calbet M, Lopez R,Cadavid MI, Loza MI, Cardenas A, Godessart N, Beleta J, Warrellow G, Ryder H(2007c) Discovery and characterization of 4′-(2-furyl)-N -pyridin-3-yl-4,5′-bipyrimidin-2′-amine (LAS38096), a potent, selective, and efficacious A2B adenosine receptor antagonist.J Med Chem 50:2732–2736

Volpini R, Costanzi S, Vittori S, Cristalli G, Klotz KN (2003) Medicinal chemistry and pharma-cology of A2B adenosine receptors. Curr Top Med Chem 3:427–443

Wang G, Rieger JM, Thompson RD (2006) Pyridyl substituted xanthines. WO Patent 2006091896Yan L, Muller CE (2004) Preparation, properties, reactions, and adenosine receptor affinities of

sulfophenylxanthine nitrophenyl esters: toward the development of sulfonic acid prodrugs withperoral bioavailability. J Med Chem 47:10311043


Zeng D, Maa T, Wang U, Feoktistov I, Biaggioni I, Belardinelli L (2003) Expression and functionof A2B adenosine receptors in the U87MG tumor cells. Drug Dev Res 58:405–411

Zhong H, Belardinelli L, Maa T, Feoktistov I, Biaggioni I, Zeng D (2004) A2B adenosine recep-tors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol30:118–125

Zhong H, Belardinelli L, Maa T, Zeng D (2005) Synergy between A2B adenosine receptors and-hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol 32:2–8

Zhong H, Wu Y, Belardinelli L, Zeng D (2006) A2B adenosine receptors induce IL-19 frombronchial epithelial cells and results in TNF-alpha increase. Am J Respir Cell Mol Biol35:587–592

[Handbook of Experimental Pharmacology] Adenosine Receptors in Health and Disease Volume 193 ||...

Documents

Transcript of [Handbook of Experimental Pharmacology] Adenosine Receptors in Health and Disease Volume 193 ||...