Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents

Richard F Clark; Tianyuan Zhang; Xiaojun Wang; Rongqi Wang; Xiaolin Zhang; Heidi S Camp; Bruce A Beutel; Hing L Sham; Yu Gui Gu

doi:10.1016/j.bmcl.2007.01.022

Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents

Bioorg Med Chem Lett. 2007 Apr 1;17(7):1961-5. doi: 10.1016/j.bmcl.2007.01.022. Epub 2007 Jan 19.

Authors

Richard F Clark¹, Tianyuan Zhang, Xiaojun Wang, Rongqi Wang, Xiaolin Zhang, Heidi S Camp, Bruce A Beutel, Hing L Sham, Yu Gui Gu

Affiliation

¹ Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. [email protected]

PMID: 17267221
DOI: 10.1016/j.bmcl.2007.01.022

Abstract

A phenyl ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isozyme selectivity. Modifications that generally impart high levels of ACC2 selectivity (>3000-fold) while maintaining excellent ACC2 potency (IC50s approximately 9-20 nM) were identified.

MeSH terms

Acetyl-CoA Carboxylase / antagonists & inhibitors*
Acetyl-CoA Carboxylase / chemistry
Chemistry, Pharmaceutical / methods*
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Humans
Hypoglycemic Agents / chemistry
Inhibitory Concentration 50
Isoenzymes / chemistry
Models, Chemical
Molecular Conformation
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Hypoglycemic Agents
Isoenzymes
ACACB protein, human
Acetyl-CoA Carboxylase