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

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

Affiliation

  • 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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