YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

Biomolecules & Therapeutics
Taedong HanHakwon Kim

Abstract

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined wi...Continue Reading

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Citations

Oct 28, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Yuanying FangRonghua Liu
Aug 6, 2019·Clinical and Experimental Pharmacology & Physiology·Hironobu TadakiTakahisa Yamada
Jan 27, 2021·International Journal of Molecular Sciences·Dong-Soon Im
Apr 27, 2021·Expert Opinion on Therapeutic Patents·Huilan LiZunhua Yang
May 29, 2021·Bioorganic Chemistry·Ajay ManaithiyaImran A Khan

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Methods Mentioned

BETA
fluorescence resonance
ELISA

Software Mentioned

Prism
WinNonlin

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