2. Academic Validation
  3. 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

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

  • J Med Chem. 2006 Jun 29;49(13):3770-3. doi: 10.1021/jm060484v.
Yu Gui Gu 1,  Moshe Weitzberg,  Richard F Clark,  Xiangdong Xu,  Qun Li,  Tianyuan Zhang,  T Matthew Hansen,  Gang Liu,  Zhili Xin,  Xiaojun Wang,  Rongqi Wang,  Teresa McNally,  Bradley A Zinker,  Ernst U Frevert,  Heidi S Camp,  Bruce A Beutel,  Hing L Sham
Affiliations

Affiliation

  • 1 Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064, USA. [email protected]
PMID: 16789734 DOI: 10.1021/jm060484v
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 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.

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