Background Free fatty acid receptor 1/G protein-coupled receptor 40 (FFA1/GPR40), is predominantly expressed in pancreatic beta cells and has drawn considerable interest as a potential therapeutic target for T2DM due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). GPR40 is also proven to be highly expressed in GLP-1-producing entero endocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. Aim HD-6277 is one such novel oral agonist of GPR40 under development as a once-a-day drug for the treatment of T2DM. Here, we studied the pharmacological effect of HD-6277 and compared the glucose-lowering effects with TAK-875(Fasiglifam), a selective FFA1/GPR40 agonist terminated in phase III clinical trials. Additionally, we compared the pharmacological potency between HD-6277, TAK-875, and LY2922470. Method hGPR40-CHO, INS-1, and NCI-H716 cell lines were used to assess the effects of HD-6277 in vitro. The in vivo effect of HD-6277 was examined in SD rats, Zucker Diabetic Fatty (ZDF) rats and Zucker rats, using an OGTT and an ITT. We also measured the GLP-1 levels on cynomolgus monkeys. Results HD-6277 showed more effective in vitro profile than TAK-875 in calcium influx assay (EC50 = 13 nM) and IP accumulation assay (EC50 = 7.5 nM). In comparison of pharmacological effects between HD-6277, TAK-875 and LY2922470, HD-6277 enhanced GSIS in INS-1 cells and SD rats. In fasted SD rats, while glibenclamide (10 mg/kg) induced hypoglycemia, HD-6277 (10-100 mg/kg) neither caused hypoglycemia nor enhanced insulin secretion. HD-6277 increased GLP-1 secretion in in vitro and in vivo, whereas TAK-875 did not. Then we evaluated the efficacy of HD-6277 (1-10 mg/kg) in rodent models of insulin resistance and type 2 diabetes. In subchronic study with male ZDF rats, HD-6277 improved glycemic control (OGTT) and GLP-1 secretion, and decreased fasting insulin levels. In male Zucker rats, an oral administrations for 10~11 weeks, HD-6277 improved insulin sensitivity (ITT) and HbA1c levels. The impaired insulin action was recovered by HD-6277 treatment in adipose tissue from the Zucker rats. In the cynomolgus monkey study, HD-6277 also showed a significant increase in GLP-1 secretion (P<0.05). Discussion The pharmacological efficacy of HD-6277 was higher than that of TAK-875 and similar to LY2922470. HD-6277 improved glycemic control in type 2 diabetic rats, which may be related to enhancement of insulin signaling and GLP-1 secretion. Therefore, we recommend HD-6277 as an effective candidate for the treatment of T2DM.
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