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

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

Journal of medicinal chemistry (2015-09-09)

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

PMID26349027

摘要

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.