118-LB: Preclinical Development of IDG-16177 as a Potent GPR40 Agonist for Treatment of Type 2 Diabetes
| Autor: | Jong Min Yoon, In-Gyu Je, Myong-Jae Lee, Don-Gil Lee, Kyung Mi An, Hyun-Jung Kwak, Chang-Hee Hong, Do-Hee Kim, Dahae Hong, Hyo-Jung Song |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist business.industry medicine.drug_class Endocrinology Diabetes and Metabolism Cmax 030209 endocrinology & metabolism Type 2 diabetes Pharmacology medicine.disease Bioavailability 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Pharmacokinetics In vivo Free fatty acid receptor 1 Internal Medicine Medicine business Receptor |
| Zdroj: | Diabetes. 69 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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 Cmax 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, Cmax,ss and AUCss 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. Disclosure J. Yoon: None. D. Kim: None. D. Lee: None. K. An: None. M. Lee: None. C. Hong: None. D. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. |
| Databáze: | OpenAIRE |
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