Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2

被引：56

作者：

Corbett, Jeffrey W. ^{[1
]}

Freeman-Cook, Kevin D. ^{[1
]}

Elliott, Richard ^{[1
]}

Vajdos, Felix ^{[1
]}

Rajamohan, Francis ^{[1
]}

Kohls, Darcy ^{[1
]}

Marr, Eric ^{[1
]}

Zhang, Hailong ^{[2
]}

Tong, Liang ^{[2
]}

Tu, Meihua ^{[1
]}

Murdande, Sharad ^{[1
]}

Doran, Shawn D. ^{[1
]}

Houser, Janet A. ^{[1
]}

Song, Wei ^{[1
]}

Jones, Christopher J. ^{[1
]}

Coffey, Steven B. ^{[1
]}

Buzon, Leanne ^{[1
]}

Minich, Martha L. ^{[1
]}

Dirico, Kenneth J. ^{[1
]}

Tapley, Susan ^{[1
]}

McPherson, R. Kirk ^{[1
]}

Sugarman, Eliot ^{[1
]}

Harwood, H. James, Jr. ^{[1
]}

Esler, William ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Groton, CT 06340 USA

[2] Columbia Univ, New York, NY 10027 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 07期

关键词：

Acetyl-CoA carboxylase; ACC; Enzyme inhibitor; Spirochromanone; ACC1; ACC2; Structure based drug discovery; Diabetes; Metabolic syndrome; COENZYME;

D O I：

10.1016/j.bmcl.2009.04.091

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2383 / 2388

页数：6

共 13 条

[1] HUMAN ACETYL-COA CARBOXYLASE - CHARACTERIZATION, MOLECULAR-CLONING, AND EVIDENCE FOR 2 ISOFORMS [J].