Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis

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.