118-LB: Preclinical Development of IDG-16177 as a Potent GPR40 Agonist for Treatment of Type 2 Diabetes

GPR40/FFAR1 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. GPR40 agonists are known to stimulate insulin secretion and reduce circulating glucose levels in a glucose-dependent manner. We investigated IDG-16177(ID11014A) as a GPR40 agonist and confirmed this drug has linear pharmacokinetic properties and is more potent than fasiglifam from in vitro and in vivo studies. In vitro metabolic stability of IDG-16177 was evaluated in mouse, rat, dog, monkey and human microsomes. IDG-16177 was metabolized mainly by CYPs in mouse, rat, monkey and human while it was metabolized mainly by UGTs in dog. Oral bioavailability of IDG-16177 was 88.1 ~ 109.9% in SD rats. The C_max and AUC values of IDG-16177 increased in a dose-proportional manner in the dose range of 1 ~ 10 mg/kg. IDG-16177 was also well exposed in monkeys after 3 mg/kg administration. Glucose lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and in various type 2 diabetes rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a single dosing study using SD and Goto-Kakizaki (GK) rats. IDG-16177 1mg/kg showed more effective in glucose tolerance than fasiglifam 10mg/kg in repeated dosing study of Zucker Diabetic Fatty (ZDF) rats. In this study, C_max,ss and AUC_ss of IDG-16177 showed approximately 10 times lower than those of fasiglifam. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes.