Themedicinal chemistry and preclinical biology of imidazopyridine-basedinhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described.A screening hit 1with low lipophilic efficiency (LipE)was optimized through two key structural modifications: (1) identificationof the pyrrolidine amide group for a significant LipE improvement,and (2) insertion of a sp3-hybridized carbon center inthe core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology.The preclinical candidate 9(PF-06424439) demonstratedexcellent ADMET properties and decreased circulating and hepatic lipidswhen orally administered to dyslipidemic rodent models. [ABSTRACT FROM AUTHOR]