Discovery of ZYDG2: a potent, selective, and safe GPR40 agonist for treatment of type 2 diabetes.

Abstract

GPR40/FFA1 receptor, predominantly expressed in pancreatic β-cells, mediates glucose-stimulated insulin secretion by free fatty acids. Fasiglifam-GPR40 agonist was terminated in phase III clinical trials due to adverse liver effects. ZYDG2 is identified as a novel, potent and selective agonist for GPR40, exhibiting EC₅₀ of 41 nM and 17 nM in cell-based functional inositol 1-phosphate-ELISA assay and Ca²⁺ mobilization assay, respectively. ZYDG2 has demonstrated dose-dependent improvement in glucose tolerance tests and increased insulin secretion in neonatal streptozotocin Wistar rats. After repeated dose administration for 15 weeks, ZYDG2 showed efficacy without tachyphylaxis. ZYDG2 significantly increased the glucose infusion rate in a hyperglycemic clamp study and demonstrated antidiabetic efficacy in mice models of type 2 diabetes mellitus, which was not reported for fasiglifam. ZYDG2 exhibited 60%-100% oral bioavailability across preclinical species, including mice, rats, dogs, and primates. Liver toxicity of fasiglifam was associated with its bile acid transporter inhibition, whereas ZYDG2 showed no inhibition (up to 300 μM). In rat acute toxicity studies, the maximum tolerated dose for ZYDG2 was 2000 mg/kg, whereas fasiglifam was tolerable up to 300 mg/kg. Fasiglifam treatment at 300 mg/kg for 10 days in rats caused a significant rise in serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin level along with vacuolation, ulceration, and red foci in liver tissue, whereas ZYDG2 showed no liver toxicity up to 300 mg/kg. Moreover, after 28 days of repeated dose treatment of ZYDG2, the no-observed-adverse-effect-level was found to be 300 mg/kg. This robust data conclusively demonstrates that ZYDG2 is a highly promising and unequivocally safe therapeutic candidate for the treatment of type 2 diabetes. SIGNIFICANCE STATEMENT: ZYDG2 is a potent, selective, and safe GPR40 agonist which may be a promising candidate for the treatment of type 2 diabetes as it has shown better efficacy and safety profile compared with fasiglifam.