Chem. Pharm. Bull. 53(4) 437—440 (2005)

ing for muscarinic receptors (m1, m2, m3, m4, m5) have been identified and cloned. Pharmacologically, four subtypes (M1, M2, M3, M4) have been defined. 6—8) Among these muscarinic receptor subtypes, M3 receptors are localized in smooth muscle and mucosal glands and mediate contraction and mucus secretion. M1 receptors, localized to the post-ganglionic cholinergic nerve terminals and glands, facilitate neurotransmission and gastric secretion. Neuronal M2 receptors provide a functional negative feedback modulation of acetylcholine (ACh) release. Extensive efforts have been directed to the identification of potent and subtype-selective M3 antagonists to complete the classification of the receptor subtypes and to provide more ideal therapeutic agents, however, few structure classes with sufficient M3 selectivity have been discovered to date. As a part of our program for developing a muscarinic M3 receptor antagonist for the treatment of pulmonary or urinary diseases, we pursued M3 antagonists that are structurally distinct from a series of 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives such as Compound A and have selectivity for M3 receptors two orders of magnitude greater than those for M1 and M2 receptors. As a result of screening of our in-house chemical collection, a thiazole-4-carboxamide derivative (1) was identified as a new lead structure. Avoiding the structural complexity of 1 due to the five chiral centers, we first replaced the perhydronaphtylmethyl moiety with a naphtylmethyl group, without regard for the binding affinity of the compound. Optimization of the compound (2) by using a solution-phase parallel synthesis method led us to the identification of M3 selective antagonists (3e, f) showing high potency (Ki ca. 1 nM) for M3 receptors and greater than 100-fold selectivity for M3 over M1 and M2 receptors. In this paper, we describe the synthesis of aminothiazole derivatives, their binding affinities for M1—M3 receptors in the binding assay, and their selectivity for M3 over M1 and M2 receptors, and discuss their structure–activity and structure–selectivity relationships.