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Arch Pharm Res. 2017 Jun;40(6):772-782. doi: 10.1007/s12272-017-0925-y. Epub 2017 Jun 8.

YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model.

Author information

1
Yuhan R&D Institute, 25 Tapsil-ro, Giheung-gu, Yongin, Gyeonggi-do, 17084, Korea.
2
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
3
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea. qwonkim@snu.ac.kr.
4
Crop Biotechnology Institute, GreenBio Science and Technology, Seoul National University, Pyeongchang, 25354, Korea. qwonkim@snu.ac.kr.

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.

KEYWORDS:

GLP-1; GPR119; Insulin; Type 2 diabetes; YH18421

PMID:
28593550
DOI:
10.1007/s12272-017-0925-y
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