Discovery of 2-Aminothiazole-4-carboxamides, a Novel Class of Muscarinic M₃ Selective Antagonists, through Solution-Phase Parallel Synthesis

抄録

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 (K_i=140 nM) for M₃ receptors in the human binding assays, we tried to improve its potency and selectivity for M₃ 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.