Structure−Activity Relationships and Molecular Modeling of 3,5-Diacyl-2,4-dialkylpyridine Derivatives as Selective A3 Adenosine Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 41; no. 17; pp. 3186 - 3201
• Main Authors: Li, An-Hu, Moro, Stefano, Melman, Neli, Ji, Xiao-duo, Jacobson, Kenneth A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 13.08.1998
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Drug Design; Humans; Iodine Radioisotopes; Kinetics; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Purinergic P1 Receptor Antagonists; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Radioligand Assay; Rats; Receptor, Adenosine A2A; Receptor, Adenosine A3; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship; Human; Rat; Nitrogen heterocycle; Rodentia; Central nervous system; Selectivity; In vitro; Modeling; Vertebrata; Mammalia; Structure activity relation; Thioester; Animal; Six membered ring; Molecular model; Affinity; Antagonist; Adenosine receptor; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980093j

The structure−activity relationships of 6-phenyl-1,4-dihydropyridine derivatives as selective antagonists at human A3 adenosine receptors have been explored (Jiang et al. J. Med. Chem. 1997, 39, 4667−4675). In the present study, related pyridine derivatives have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K i values in the nanomolar range were observed for certain 3,5-diacyl-2,4-dialkyl-6-phenylpyridine derivatives in displacement of [125I]AB-MECA (N 6-(4-amino-3-iodobenzyl)-5‘-N-methylcarbamoyladenosine) at recombinant human A3 adenosine receptors. Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A2A receptors. Structure−activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. A 4-phenylethynyl group did not enhance A3 selectivity of pyridine derivatives, as it did for the 4-substituted dihydropyridines. At the 2- and 4-positions ethyl was favored over methyl. Also, unlike the dihydropyridines, a thioester group at the 3-position was favored over an ester for affinity at A3 adenosine receptors, and a 5-position benzyl ester decreased affinity. Small cycloalkyl groups at the 6-position of 4-phenylethynyl-1,4-dihydropyridines were favorable for high affinity at human A3 adenosine receptors, while in the pyridine series a 6-cyclopentyl group decreased affinity. 5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 38, was highly potent at human A3 receptors, with a K i value of 20 nM. A 4-propyl derivative, 39b, was selective and highly potent at both human and rat A3 receptors, with K i values of 18.9 and 113 nM, respectively. A 6-(3-chlorophenyl) derivative, 44, displayed a K i value of 7.94 nM at human A3 receptors and selectivity of 5200-fold. Molecular modeling, based on the steric and electrostatic alignment (SEAL) method, defined common pharmacophore elements for pyridine and dihydropyridine structures, e.g., the two ester groups and the 6-phenyl group. Moreover, a relationship between affinity and hydrophobicity was found for the pyridines.