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

  • ACS Med Chem Lett. 2018 Apr 10;9(5):457-461. doi: 10.1021/acsmedchemlett.8b00073.
Santhosh F Neelamkavil  1 ,  Andrew W Stamford  1 ,  Timothy Kowalski  1 ,  Dipshikha Biswas  1 ,  Craig Boyle  1 ,  Samuel Chackalamannil  1 ,  Yan Xia  1 ,  Charles Jayne  1 ,  Bernard Neustadt  1 ,  Jinsong Hao  1 ,  Hong Liu  1 ,  Xing Dai  1 ,  Hana Baker  1 ,  Brian Hawes  1 ,  Kim O'Neill  1 ,  Huadong Tang  1 ,  William J Greenlee  1
Affiliations
  • 1. MRL, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 29795759 DOI: 10.1021/acsmedchemlett.8b00073
Abstract

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.

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