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 β cells. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received much interest for the treatment of type 2 diabetes. Here, we identified a novel small-molecule GPR119 agonist, YH18421 and evaluated its therapeutic potential. 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-4 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. We also observed that YH18421 inhibited weight gain during 4 weeks of administration in DIO mice. These data demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and combination with the DPP-IV inhibitor maybe an effective strategy for the treatment of type 2 diabetes.
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This study was supported by a Grant of Korean Health Technology R&D project, Ministry of Health & Welfare, Republic of Korea (HI14C1007).
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Yoo Hoi Park, Hyun Ho Choi, Dong Hoon Lee, Soo Yong Chung, Na Yeon Yang, Do Hoon Kim, Mi Kyeong Ju, Tae Dong Han and Su Youn Nam are employees of Yuhan Corporation.
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Park, Y.H., Choi, H.H., Lee, D.H. et al. YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model. Arch. Pharm. Res. 40, 772–782 (2017). https://doi.org/10.1007/s12272-017-0925-y
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DOI: https://doi.org/10.1007/s12272-017-0925-y