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

被引：55

作者：

Gu, Yu Gui ^{[1
]}

Weitzberg, Moshe ^{[1
]}

Clark, Richard F. ^{[1
]}

Xu, Xiangdong ^{[1
]}

Li, Qun ^{[1
]}

Zhang, Tianyuan ^{[1
]}

Hansen, T. Matthew ^{[1
]}

Liu, Gang ^{[1
]}

Xin, Zhili ^{[1
]}

Wang, Xiaojun ^{[1
]}

Wang, Rongqi ^{[1
]}

McNally, Teresa ^{[1
]}

Camp, Heidi ^{[1
]}

Beutel, Bruce A. ^{[1
]}

Sham, Hing L. ^{[1
]}

机构：

[1] Abbott Labs, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 13期

关键词：

D O I：

10.1021/jm060484v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 IC50 < 20 nM and > 1000-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.

引用

页码：3770 / 3773

页数：4

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