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Pyran template approach to the design of novel A 3 adenosine receptor antagonists
Author(s) -
Li AnHu,
Ji Xiaoduo,
Kim Hak Sung,
Melman Neli,
Jacobson Kenneth A.
Publication year - 1999
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199912)48:4<171::aid-ddr4>3.0.co;2-5
Subject(s) - chemistry , stereochemistry , receptor , substituent , pyran , adenosine receptor , pyridine , structure–activity relationship , adenosine , in vitro , biochemistry , medicinal chemistry , agonist
A 3 adenosine receptor antagonists have potential as anti‐inflammatory, anti‐asthmatic, and anti‐ischemic agents. We previously reported the preparation of chemical libraries of 1,4‐dihydropyridine (DHP) and pyridine derivatives and identification of members having high affinity at A 3 adenosine receptors. These derivatives were synthesized through standard three‐component condensation/oxidation reactions, which permitted versatile ring substitution at five positions, i.e., the central ring served as a molecular scaffold for structurally diverse substituents. We extended this template approach from the DHP series to chemically stable pyran derivatives, in which the ring NH is replaced by O and which is similarly derived from a stepwise reaction of three components. Since the orientation of substituent groups may be conformationally similar to the 1,4‐DHPs, a direct comparison between the structure activity relationships of key derivatives in binding to adenosine receptors was carried out. Affinity at human A 3 receptors expressed in CHO cells was determined vs. binding of [ 125 I]AB‐MECA (N 6 ‐(4‐amino‐3‐iodobenzyl)‐5′‐N‐methylcarbamoyladenosine). There was no potency‐enhancing effect, as was observed for DHPs, of 4‐styryl, 4‐phenylethynyl, or 6‐phenyl substitutions. The most potent ligands in this group in binding to human A 3 receptors were 6‐methyl and 6‐phenyl analogs, 3a (MRS 1704) and 4a (MRS 1705), respectively, of 3,5‐diethyl 2‐methyl‐4‐phenyl‐4 H ‐pyran‐3,5‐dicarboxylate, which had K i values of 381 and 583 nM, respectively. These two derivatives were selective for human A 3 receptors vs. rat brain A 1 receptors by 57‐fold and 24‐fold, respectively. These derivatives were inactive in binding at rat brain A 2A receptors, and at recombinant human A 2B receptors displayed K i values of 17.3 and 23.2 μM, respectively. The selectivity, but not affinity, of the pyran derivatives in binding to the A 3 receptor subtype was generally enhanced vs. the corresponding DHP derivatives. Drug Dev. Res. 48:171–177, 1999. Published 1999 Wiley‐Liss, Inc.