Type 2 Diabetes Mellitus (T2DM) is a growing worldwide epidemic currently affecting an estimated 300 million people. Despite a number of diabetic therapies available nowadays, there remains a significant unmet medical need for additional therapies. G protein-coupled receptor 40 (GPR40) is a free fatty acid receptor that is highly expressed in pancreatic β cells and mediates free fatty acid-induced and glucose-dependent, insulin secretion (GDIS). GPR40 agonists, by acting <i>via</i> GDIS pathway which mechanistically leads to reduced hypoglycemia risk, may offer advantages to commonly used antidiabetic agents. Since deorphanization in 2003, development of small molecule GPR40 agonists has been extensively reported. Clinical data from GPR40 agonists TAK-875 and AMG 837 have also demonstrated robust glucose control in T2DM patients. In this presentation, design, synthesis, and biological evaluation of a novel series of 5-substituted-2,4-oxazolidinediones as potential GPR40 agonists, which led to the discovery of several selective and potent GPR40 agonists, will be discussed.

Discovery of 5-substituted-2,4-oxazolidinediones as potent GPR40 agonists for treatment of type II diabetes

251st National Meeting (2016)

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