Discovery of MK-8282 as a Potent G‑Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy