Discovery of 2-Aminothiazole-4-carboxamides, a Novel Class of Muscarinic M_3 Selective Antagonists, through Solution-Phase Parallel Synthesis

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Synthesis and structure-activity relationship of a new class of muscarinic M_3 selective antagonists were described. In the course of searching for a muscarinic M_3 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=140nM) for M_3 receptors in the human binding assays, we tried to improve its potency and selectivity for M_3 over M_1 and M_2 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 M_3 selective antagonists in this class.
公益社団法人日本薬学会の論文
2005-04-01