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

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.