期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 7, 页码 2383-2388出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.04.091
关键词
Acetyl-CoA carboxylase; ACC; Enzyme inhibitor; Spirochromanone; ACC1; ACC2; Structure based drug discovery; Diabetes; Metabolic syndrome
资金
- NIDDK NIH HHS [R01 DK067238-04, R01 DK067238] Funding Source: Medline
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.
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