1 research outputs found
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