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KMID : 0043320170400060772
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Archives of Pharmacal Research
2017 Volume.40 No. 6 p.772 ~ p.782
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YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model
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Park Yoo-Hoi
Choi Hyun-Ho
Lee Dong-Hoon
Chung Soo-Yong
Yang Na-Yeon
Kim Do-Hoon
Ju Mi-Kyeong
Han Tae-Dong
Nam Su-Youn
Kim Kyu-Won
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Abstract
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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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KEYWORD
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GPR119, YH18421, GLP-1, Insulin, Type 2 diabetes
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