Identification and Synthesis of Novel Inhibitors of Acetyl-CoA Carboxylase with in Vitro and in Vivo Efficacy on Fat Oxidation

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• 作者：Stefanie Keil ; Marco Mller ; Gerhard Zoller ; Guido Haschke ; Katrin Schroeter ; Maike Glien ; Sven Ruf ; Ingo Focken ; Andreas W. Herling ; Dieter Schmoll
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 23, 2010
• 年：2010
• 卷：53
• 期：24
• 页码：8679-8687
• 全文大小：969K
• 年卷期：v.53,no.24(December 23, 2010)
• ISSN：1520-4804

文摘

Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat utilization and their inhibition is considered to improve aspects of the metabolic syndrome. To identify pharmacological inhibitors of ACC1/2, a high throughput screen was performed which resulted in the identification of the lead compound 3 (Gargazanli, G.; Lardenois, P.; Frost, J.; George, P. Patent WO9855474 A1, 1998) as a moderate selective ACC2 inhibitor. Optimization of 3 led to 4m (Zoller, G.; Schmoll, D.; Mueller, M.; Haschke, G.; Focken, I. Patent WO2010003624 A2, 2010) as a submicromolar dual ACC1/2 inhibitor of the rat and human isoforms. 4m possessed favorable pharmacokinetic parameters. This compound stimulated fat oxidation in vivo and reduced plasma triglyceride levels in a rodent model after subchronic administration. 4m is a suitable tool compound for the elucidation of the pharmacological potential of ACC1/2 inhibition.