GPR40 is one of GPCRs predominantly expressed in pancreatic β-cells. Free fatty acids activate GPR40 as natural ligands and insulin secretion is promoted depending on the plasma glucose level. GPR40 agonist is expected as an effective anti-diabetic drug with the low risk of hypoglycemia. To date, several potent GPR40 agonists have been reported. Most of them have phenyl propionic acid moiety. The methylene protons of the phenyl propinonic acid are known as metabolic soft spot, and many of GPR40 agonists have a substituent on the benzyl position to improve oral bioavailability. Although some acid surrogates for GPR40 agonists have been reported, no effective agonist having an acid surrogate directly bonding with the phenyl ring is known. As the results of our exploration of acid surrogates, we found the isothiazole S-oxide worked as a good acid group for orally available GPR40 agonists. Further optimization of isothiazole derivatives led to the discovery of MR1704 as a clinical candidate. In this presentation, we will describe the exploration of acid surrogates, lead identification & optimization, SAR of isothiazole-based GPR40 agonists and the profiles of MR1704.

Discovery of clinical candidate MR1704: A novel isothiazole based GPR40 agonist for diabetes

254th National Meeting (2017)

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