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
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
收藏
页码:2383 / 2388
页数:6
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