Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound (hMGAT2 IC = 175 nM) as a hit. Compound had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors , , and that are stable to liver microsomal metabolism. After triaging out due to its inferior potency, pharmacokinetics, and structure-based liabilities and tetrazole due to its inferior channel liability profile, (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.