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

作者：Kentaro Futatsugi, Daniel W. Kung, Suvi T. M. Orr, Shawn Cabral, David Hepworth, Gary E. Aspnes, Scott J. Bader, Jianwei Bian, Markus Boehm, Philip A. Carpino, Steven B. Coffey, Matthew Dowling, Michael Herr, Wenhua Jiao, Sophie Y. Lavergne, Qifang Li, Ronald W. Clark, Derek M. Erion, Kou Kou, Kyuha Lee, Brandon Pabst, Sylvie M. Perez, Julie J. Purkal, Csilla C. Jorgensen, Theunis C. Goosen, J Gosset, Mark Niosi, John C. Pettersen, Jeffrey A. Pfefferkorn, Kay Ahn, Bryan Goodwin · 发表于：Journal of Medicinal Chemistry · 年份：2015 · DOI：10.1021/acs.jmedchem.5b01006 · 被引用次数：85 · 研究领域：Lipid metabolism and biosynthesis、Peroxisome Proliferator-Activated Receptors、Metabolism, Diabetes, and Cancer

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 sp(3)-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.