title: Discovery of 2-aminothiazole-4-carboxamides, a novel class of muscarinic M(3) selective antagonists, through solution-phase parallel synthesis.
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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: Yufu
authors.initials: Y
authors.lastname: Sagara
authors.forename: Morihiro
authors.initials: M
authors.lastname: Mitsuya
authors.forename: Minaho
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ogino
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mase
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D043587:Receptor, Muscarinic M3 / Q000187:drug effects*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000577:Amides; D007202:Indicators and Reagents; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D013844:Thiazoles