GPR40 is known as free fatty acid receptor 1. Currently, HD-6277, a novel GPR40 agonist, is being developed by Hyundai Pharm in first in human study. The aim of this study was to determine the effects of the novel GPR40 agonist. HD-6277 is a highly potent, selective and orally available small molecule agonist. The potency was measured in vitro and in vivo studies. In vitro potency was determined by HD-6277, TAK-875 and GW95(EC50, <10 nM, 27 nM and 14 nM) in stably hGPR40 expressed CHO cells. Selective GPR40 activity of HD-6277 was evaluated by GPCR panel assay.In vivo glucose lowering effect was determined by oral glucose tolerance test (OGTT) and HbA1c in Sprague-Dawley (SD) rats and various type 2 diabetes rats, respectively. Oral administration of HD-6277 (0.1∼10 mg/kg) once daily reduced plasma glucose excursion and enhanced insulin secretion in GK, DIO, OLETF and ZDF rats. Antidiabetic efficacy compared with Metformin, Glimepiride, Linagliptin, Empagliflozin, Rosiglitazone and Fasiglifam respectively. HD-6277 treatment showed potent anti-hyperglycemic effects than commercially available antidiabetic drugs. GSIS was assessed in INS-1 cells and rats with sulfonylurea and glinides. HD-6277 enhanced insulin excursion in high glucose condition, whereas in low glucose circumstance was not, thus hypoglycemic risk was low. Repeat dosing for 7day in SD rats, glibenclamide (10 mg/kg) and nateglinide (50 mg/kg) caused hypoglycemia but HD-6277 (100 mg/kg) was not.
In conclusion, HD-6277 shows a promising new drug candidates to treat type 2 diabetes mellitus.
D. Kim: Employee; Self; Hyundai Pharm. Corp. C. Kim: Employee; Self; Hyundai Pharm. corp.. H. Choi: None. G. Yang: Employee; Self; Hyundai Pharm. CORP. S. Kang: Employee; Self; Hyundai Pharm. corp. S. Lee: Employee; Self; Hyundai Pharm. CORP. K. Lim: Employee; Self; Hyundai Pharm. corp. M. Park: Employee; Self; Hyundai Pharm.corp. D. Kim: Employee; Self; Hyundai Pharm. CORP. J. Rhee: Employee; Self; Hyundai Pharm. corp..