Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes
| Autor: | Charles Lee Jayne, Hong Liu, Yan Xia, Santhosh Neelamkavil, William J. Greenlee, Hana Baker, Brian Hawes, Kim O’Neill, Andrew Stamford, Timothy J. Kowalski, Xing Dai, Jinsong Hao, Samuel Chackalamannil, Huadong Tang, Dipshikha Biswas, Bernard R. Neustadt, Craig D. Boyle |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist 010405 organic chemistry medicine.drug_class Chemistry Organic Chemistry Type 2 diabetes Pharmacology medicine.disease 01 natural sciences Biochemistry 0104 chemical sciences 03 medical and health sciences 030104 developmental biology GPR119 Sitagliptin Drug Discovery medicine Potency Glucose homeostasis Receptor medicine.drug G protein-coupled receptor |
| Zdroj: | ACS Medicinal Chemistry Letters. 9:457-461 |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|