Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

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• 作者：Kentaro Futatsugi ; Daniel W. Kung ; Suvi T. M. Orr ; Shawn Cabral ; David Hepworth ; Gary Aspnes ; Scott Bader ; Jianwei Bian ; Markus Boehm ; Philip A. Carpino ; Steven B. Coffey ; Matthew S. Dowling ; Michael Herr ; Wenhua Jiao ; Sophie Y. Lavergne ; Qifang Li ; Ronald W. Clark ; Derek M. Erion ; Kou Kou ; Kyuha Lee ; Brandon A. Pabst ; Sylvie M. Perez ; Julie Purkal ; Csilla C. Jorgensen ; Theunis C. Goosen ; James R. Gosset ; Mark Niosi ; John C. Pettersen ; Jeffrey A. Pfefferkorn ; Kay Ahn ; Bryan Goodwin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7173-7185
• 全文大小：513K
• ISSN：1520-4804

文摘

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp³-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.