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 <b>1</b> (hMGAT2 IC<sub>50</sub> = 175 nM) as a hit. Compound <b>1</b> 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 <b>21f</b>, <b>21s</b>, and <b>28e</b> that are stable to liver microsomal metabolism. After triaging out <b>21f</b> due to its inferior <i>in vivo</i> potency, pharmacokinetics, and structure-based liabilities and tetrazole <b>28e</b> due to its inferior channel liability profile, <b>21s</b> (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.