Discovery of a Potent, Selective, and Orally Efficacious Pyrimidinooxazinyl Bicyclooctaneacetic Acid Diacylglycerol Acyltransferase-1 Inhibitor

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• 作者：Alan M. Birch* ; Susan Birtles ; Linda K. Buckett ; Paul D. Kemmitt ; Graham J. Smith ; Tim J. D. Smith ; Andrew V. Turnbull ; Steven J. Y. Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 26, 2009
• 年：2009
• 卷：52
• 期：6
• 页码：1558-1568
• 全文大小：234K
• 年卷期：v.52,no.6(March 26, 2009)
• ISSN：1520-4804

文摘

Inhibition of DGAT-1 is increasingly seen as an attractive mechanism with the potential for treatment of obesity and other elements of the metabolic syndrome. We report here a bicyclooctaneacetic acid derivative in the pyrimidinooxazine structural class of DGAT-1 inhibitors that has good potency, selectivity, and pharmacokinetic characteristics across a variety of species. This compound is an effective inhibitor of DGAT-1 in both intestinal and adipose tissue, which results in a reduction in body weight or body weight gain following oral administration in both mouse and rat models of dietary-induced obesity.