Synthesis and Structure−Activity Relationships of N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy Derivatives as Selective Acetyl-CoA Carboxylase 2 Inhibitors
Journal of Medicinal Chemistry2006Vol. 49(13), pp. 3770–3773
Citations Over TimeTop 14% of 2006 papers
Yu Gu, Moshe Weitzberg, Richard F. Clark, Xiangdong Xu, Qun Li, Tianyuan Zhang, Terkel Hansen, Gang Liu, Zhili Xin, Xiaojun Wang, Rongqi Wang, Teresa McNally, Heidi S. Camp, Bruce A. Beutel, Hing L. Sham
Abstract
A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC501000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
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