Discovery of 2-aminothiazole-4-carboxamides, a novel class of muscarinic M(3) selective antagonists, through solution-phase parallel synthesis |
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Authors: | Sagara Yufu Mitsuya Morihiro Uchiyama Minaho Ogino Yoshio Kimura Toshifumi Ohtake Norikazu Mase Toshiaki |
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Institution: | Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan. |
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Abstract: | 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)=140 nM) 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. |
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