Discovery of 2-aminothiazole-4-carboxamides, a novel class of muscarinic M3 selective antagonists, through solution-phase parallel synthesis

Abstract

Synthesis and structure-activity relationship of a new class of muscarinic M3 selective antagonists were described. In the course of searching for a muscarinic M3 antagonist with a structure distinct from those of the 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives, we identified a thiazole-4-carboxamide derivative (1) as a lead compound in our in-house chemical collection. Since this compound (1) showed relatively low binding affinity (K1 = 140 nM) for M3 receptors in the human binding assays, we tried to improve its potency and selectivity for M 3 over M1 and M2 receptors by derivatization of 1 through a combinatorial approach. A solution-phase parallel synthesis effectively contributed to the optimization of each segment of 1. Thus, we have identified a cyclooctenylmethyl derivative (3e) and a cyclononenylmethyl derivative (3f) as representative M3 selective antagonists in this class. © 2005 Pharmaceutical Society of Japan.