DR10627, a Novel Dual Glucagon‑like Peptide‑1 and Gastric Inhibitory Polypeptide Receptor Agonist for the Treatment of Obesity and Type 2 Diabetes Mellitus

Introduction: Diabetes and obesity are momentous risk factors threatening people's lives and health.Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss.Coagonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss.Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it.Methods: The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro.The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys.The OGTTs were performed in Sprague-Dawley (SD) rats.The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic (db/db) mice for 4 weeks.The effects of anti-obesity and improving metabolism of DR10627 were evaluated by repeated administration of DR10627 in diet-induced obesity (DIO) mice for 57 days.Results: DR10627 had the capacity to activate both GLP-1R and GIPR in vitro.The terminal half-life of DR10627 was found to be approximately 4.19-5.8h in cynomolgus monkeys.DR10627 had a great improvement in oral glucose tolerance in SD rats.Moreover, DR10627 had a potent glucose-lowering effect in db/db mice, and the hypoglycemic effect of 18 nmol/kg DR10627 was better than that of 50 nmol/kg liraglutide.In addition, 10 and 30 nmol/kg DR10627 possessed the ability of potentiating the weight-loss, lipidlowing efficacy and improving metabolism to a greater extent than 80 nmol/kg liraglutide.Conclusion: Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and db/db mice, and substantial body weight reduction and metabolism improvement in DIO mice.DR10627 is a promising agent deserving further investigation for the treatment of type 2 diabetes and obesity.