123-LB: IDG-16177, a Potent, Orally-Bioavailable GPR40 Agonist, Improves Glycemic Control and Glucose-Stimulated Insulin Secretion in Preclinical Studies

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. Supplement_1
• Main Authors: YOON, JONGMIN, LEE, DON-GIL, KIM, JUNG HO, HONG, DAHAE, SHIN, CHORONG, JANG, EUNHYE, KIM, JISU, SONG, HAENGJIN, LEE, SEOLHEE, JUN, YEARIN, AN, KYUNGMI, HONG, CHANG-HEE, KWAK, HYUN-JUNG, JE, IN-GYU, SONG, HYO-JUNG
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01-06-2021
• Subjects: Agonists; Beta cells; Bioavailability; Blood glucose; Diabetes; Diabetes mellitus (non-insulin dependent); Dosage; G protein-coupled receptors; Glucagon; Glucose; Glucose tolerance; Insulin; Insulin secretion; Pancreas; Pharmacokinetics; Rodents
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db21-123-LB

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. Currently, IDG-16177, as a GPR40 agonist, is being developed by ildong Pharma in first-in-human study. IDG-16177 is a high potency and orally available small molecule agonist. IDG-16177 confirmed linear pharmacokinetic properties and is more potent than fasiglifam from in vivo studies. The oral bioavailability of IDG-16177 was 84.3, 75.4, and 71% in mice, rats, and monkeys, showing high oral absolute bioavailability in preclinical species. The Cmax and AUC values of IDG-16177 increased in a dose-proportional manner in a dose range of 0.3 to 10 mg/kg in mice and rats and 0.3 to 3 mg/kg in monkeys. In vivo long-term glucose-lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a multiple dosing study using SD and OLETF rats. In both in vivo tests, IDG-16177 0.3 mg/kg showed similar effective in glucose tolerance fasiglifam 10 mg/kg, respectively. In addition, IDG-16177 had a positive effect on fasting blood glucose, insulin, and glucagon in the long-term administration of OLETF rats. In these study, Cmax,ss of IDG-16177 showed approximately 60 times lower than those of fasiglifam and AUCss of IDG-16177 showed approximately 170 times lower than those of fasiglifam. In another study, the Glucose-stimulated insulin secretion effect of IDG-16177 was assessed in Male SD rat. IDG-16177 1 mg/kg showed similar effective in insulin secretion fasiglifam 10 mg/kg. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes.
Disclosure
J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. H. Song: None. S. Lee: None.