pf-06424439 and Dyslipidemias

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.

Topics: Animals; Cyclopropanes; Diacylglycerol O-Acyltransferase; Dogs; Dyslipidemias; Hepatocytes; Humans; Imidazoles; Lipid Metabolism; Male; Mice, Knockout; Pyridines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, LDL; Sf9 Cells; Spodoptera; Stereoisomerism; Structure-Activity Relationship