Discovery of 12 (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable in vitro profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight. Subsequent studies in MGAT2 knockout mice with the lead candidate 12 (BMS-986172) showed on-target- and mechanism-based pharmacology. Moreover, its favorable pharmacokinetic (PK) profile and the lack of species variability in the glucuronidation potential resulted in a greater confidence level in the projection of a low dose for achieving targeted efficacious exposures in humans. Consistent with these projections, PK data from a phase 1 trial confirmed that targeted efficacious exposures could be achieved at a low dose in humans, which supported compound 12 as our second and potentially superior development candidate for the treatment of various metabolic disorders.

Automated summary

A series of novel tetrazolone compounds with potent MGAT2 inhibitory activity and favorable in vitro profiles were discovered. These compounds showed significant reduction in food intake and body weight in mouse models. One lead compound (12, BMS-986172) exhibited on-target- and mechanism-based pharmacology in MGAT2 knockout mice, and its favorable pharmacokinetic profile suggested a low dose for achieving targeted efficacious exposures in humans. Phase 1 trial confirmed the achievement of targeted efficacious exposures at a low dose in humans, supporting compound 12 as a potential development candidate for metabolic disorders treatment.