Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity a

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• 作者：Yimin Qian ; Stanley J. Wertheimer ; Mushtaq Ahmad ; Adrian Wai-Hing Cheung ; Fariborz Firooznia ; Matthew M. Hamilton ; Stuart Hayden ; Shiming Li ; Nicholas Marcopulos ; Lee McDermott ; Jenny Tan ; Weiya Yun ; Liang Guo ; Anjula Pamidimukkala ; Yingsi Chen ; Kuo-Sen Huang ; Gwendolyn B. Ramsey ; Toni Whittard ; Karin Conde-Knape ; Rebecca Taub ; Cristina M. Rondinone ; Jefferson Tilley ; David Bolin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2433-2446
• 全文大小：1105K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC₅₀ = 57 nM; CHO-K1 cell triglyceride formation assay, EC₅₀ = 0.5 渭M) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, PO, qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).