Abstract
A3 adenosine receptor (A3AR) ligands have been modified to optimize their interaction with the A3AR. Most of these modifications have been made to the N6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A3AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A3AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A3AR antagonists. Probably due to the “enigmatic” physiological role of A3AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A3AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.
Keywords
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Abbreviations
- ADME:
-
Absorption, distribution, metabolism, and excretion
- AR:
-
Adenosine receptor
- b:
-
Bovine
- cAMP:
-
Cyclic adenosine monophosphate
- CHO cells:
-
Chinese hamster ovary cells
- Cl–IB–MECA:
-
2-Chloro-N 6-(3-iodobenzyl)-5′-N-methylcarboxamido- adenosine
- CoMFA:
-
Comparative molecular field analysis
- CVT-3146:
-
1-{9-[(4S, 2R, 3R, 5R)-3,4-Dihydroxy-5-(hydroxymethyl) oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- methylcarboxamide
- DBXRM:
-
7-β-d-Ribofuronamide
- DHP:
-
1,4-Dihydropyridine
- Et:
-
Ethyl
- GPCR:
-
G-protein-coupled receptor
- h:
-
Human
- HEK293 cells:
-
Human embryonic kidney 293 cells
- I–AB–MECA:
-
N 6-(4-Amino-3-iodobenzyl)-5′-N-methylcabroxamidoa- denosine
- IB–MECA:
-
N 6-(3-Iodobenzyl)-5′-N-methylcarboxamidoadenosine
- KF-26777:
-
2-(4-Bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
- LJ-529:
-
2-Chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′- methyluronamide
- LJ-1251:
-
(2R, 3R, 4S)-2-(2-Chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol
- LJ-1416:
-
(2R, 3R, 4S)-2-(2-Chloro-6-(3-chlorobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol
- LUF6000:
-
N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c] quinolin-4-amine
- Me:
-
Methyl
- MRE-3005-F20:
-
5-N-(4-Methoxyphenylcarbamoyl)amino-8-ethyl-2-(2-furyl) pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
- MRE-3008-F20:
-
5-N-(4-Methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl) pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
- MRS1191:
-
1,4-Dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3, 5-pyridinedicarboxylic acid, 3-ethyl 5-(phenylmethyl) ester
- MRS1220:
-
N-[9-Chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-yl]benzeneacetamide
- MRS1292:
-
(2R, 3R, 4S, 5S)-2-[N 6-3-Iodobenzyl)adenos-9′-yl]-7-aza-1-oxa-6-oxospiro[4.4]-nonan-4,5-diol
- MRS1523:
-
5-Propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)- 6-phenylpyridine-5-carboxylate
- MRS3558:
-
(1′ S, 2′ R, 3′ S, 4′ R, 5′ S)-4-{2-Chloro-6-[(3-iodophenylmethyl) amino]purin-9-yl}-1-(methylaminocarbonyl)bicyclo-[3.1.0]-hexane-2,3-diol
- MRS3777:
-
2-(Phenyloxy)-N 6-cyclohexyladenine
- MRS5127:
-
(1′ R, 2′ R, 3′ S, 4′ R, 5′ S)-4′-[2-chloro-6-(3-iodobenzylamino)-purine]-2′, 3′-O-dihydroxybicyclo-[3.1.0]hexane
- MRS5147:
-
(1′ R, 2′ R, 3′ S, 4′ R, 5′ S)-4′-[2-chloro-6- (3-bromobenzylamino)-purine]-2′, 3′-O-dihydroxybicyclo- [3.1.0]hexane
- MRS5151:
-
(1′ S, 2′ R, 3′ S, 4′ S, 5′ S)-4′-[6-(3-chlorobenzylamino)-2-(5-hydroxycarbonyl-1-pentynyl)-9-yl]-2′, 3′-dihydroxybicyclo[3.1.0]hexane-1′-carboxylic acid N-methylamide
- NECA:
-
adenosine 5′-N-ethyluronamide
- OT-7999:
-
5-n-Butyl-8-(4-trifluoromethylphenyl)-3H-[1,2,4]triazolo-[5,1-i]purine
- Pr:
-
Propyl
- PSB-10:
-
8-Ethyl-1,4,7,8-tetrahydro-4-methyl-2-(2,3,5-trichlorophenyl)-5H-imidazo[2,1-i]purin-5-one
- PSB-11:
-
(R)-4-Methyl-8-ethyl-2-phenyl-4,5,7,8-tetrahydro-1H- imidazo[2,1-i]purin-5-one
- QSAR:
-
Quantitative structure–activity relationships
- r:
-
Rat
- SARs:
-
Structure–activity relationships
- TM:
-
Transmembrane domain
- VUF 5574:
-
N-(2-Methoxyphenyl)-N ′-(2-(3-pyridyl)quinazolin-4-yl)urea
- VUF 8504:
-
4-Methoxy-N-(3-(2-pyridinyl)-1-isoquinolinyl)benzamide
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Acknowledgements
This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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Jacobson, K.A., Klutz, A.M., Tosh, D.K., Ivanov, A.A., Preti, D., Baraldi, P.G. (2009). Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_5
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