Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes
Santhosh F. Neelamkavil, Andrew W. Stamford, Timothy Kowalski, Dipshikha Biswas, Craig Boyle, Samuel Chackalamannil, Yan Xia, Charles Jayne, Bernard Neustadt, Jinsong Hao, Hong Liu, Xing Dai, Hana Baker, Brian Hawes, Kim O’Neill, Huadong Tang, William J. Greenlee
文献索引：10.1021/acsmedchemlett.8b00073
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摘要
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.