Identification of YH18421, a novel GPR119 agonist for the treatment of type 2 diabetes

Abstract

G-protein-coupled receptor 119 (GPR119) represents a promising target for the treatment of type 2 diabetes as it can increase both GLP-1 secretion from intestinal L cells and glucose-stimulated insulin secretion (GSIS) from pancreatic cells. Due to these dual mechanism of action, the development of small molecule GPR119 agonists have received much interest for the treatment of type 2 diabetes. Here, YH18421, a novel small-molecule GPR119 agonist was identified and its therapeutic potential was evaluated. YH18421 specifically activated human GPR119 with high potency and potentiated GLP-1 secretion and GSIS in vitro cell based systems. In normal mice, single oral administration of YH18421 improved glucose tolerance. Combined treatment of YH18421 and the DPP-IV inhibitor augmented both plasma active GLP-1 levels and glycemic control. In diet induced obese (DIO) mice model, glucose lowering effect of YH18421 was maintained after 4 weeks of repeat dosing and YH18421 acted additively with DPP-IV inhibitor. YH18421 also inhibited weight gain during 4 weeks of administration in DIO mice. These results demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and suggest that YH18421 alone or in combination with a DPP-IV inhibitor, represents a new type of an oral GLP-1 based therapy for the treatment of type 2 diabetes