Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis
Kentaro Futatsugi, Shawn Cabral, Daniel W. Kung, Kim Huard, Esther C. Y. Lee, Markus Boehm, Jonathan Bauman, Ronald W. Clark, Steven B. Coffey, Collin Crowley, Anne‐Marie Dechert‐Schmitt, Matthew Dowling, Robert Dullea, J Gosset, Amit S. Kalgutkar, Kou Kou, Qifang Li, Yajing Lian, Paula M. Loria, Allyn T. Londregan, Mark Niosi, Christine C. Orozco, John C. Pettersen, Jeffrey A. Pfefferkorn, Jana Polívková, Trenton T. Ross, Raman Sharma, Ingrid A. Stock, Gregory J. Tesz, Hanna M. Wisniewska, Bryan Goodwin, David A. Price
Abstract
Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.