Pyran template approach to the design of novel A(3) adenosine receptor antagonists

A(3) adenosine receptor antagonists have potential as anti-inflammatory, an ti-asthmatic, and anti-ischemic agents. We previously reported the preparat ion of chemical libraries of 1, 1-dihydropyridine (DHP) and pyridine deriva tives and identification of members having high affinity at A(3) adenosine receptors. These derivatives were synthesized through standard three-compon ent condensation/oxidation reactions, which permitted versatile ring substi tution at five positions, i.e., the central ring served as a molecular scaf fold for structurally diverse substituents. We extended this template appro ach from the DHP series to chemically stable pyran derivatives, in which th e ring NH is replaced by O and which is similarly derived from a stepwise r eaction of three components. Since the orientation of substituent groups ma y be conformationally similar to the 1,4-DH Ps, a direct comparison between the structure activity relationships of key derivatives in binding to aden osine receptors was carried out. Affinity at human Ag receptors expressed i n CHO cells was determined vs, binding of [I-125]AB-MECA (N-6-(4-amino-3-io dobenzyl)-5'-N-methyl-carbamoyladenosine). There was no potency-enhancing e ffect, 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-4H-pyran-3,5-dicarbox y which had K-i values of 381 and 583 nM, respectively. These two derivativ es were selective for human A3 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 dis played K-i values of 17.3 and 23.2 mu M, respectively. The selectivity, but not affinity of the pyran derivatives in binding to the A(3) receptor subt ype was generally enhanced vs. the corresponding DHP derivatives. Drug Dev. Res. 48:171-177, 1999. Published 1999 Wiley-Liss, Inc.(+)