Biomol Ther.  2018 Mar;26(2):201-209. 10.4062/biomolther.2018.011.

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

• Han T
• Lee BM
• Park YH
• Lee DH
• Choi HH
• Lee T
• Kim H

• KMID: 2429060
• DOI: http://doi.org/10.4062/biomolther.2018.011

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 with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

Keyword

Type 2 diabetes; GPR119 agonist; GLP-1; Insulin; YH18968

MeSH Terms

Adenosine Monophosphate
Administration, Oral
Animals
Diabetes Mellitus, Type 2*
Diet
Dipeptidyl Peptidase 4
Enteroendocrine Cells
Gastrointestinal Tract
Glucagon-Like Peptide 1
Glucose
GTP-Binding Proteins*
Insulin
Islets of Langerhans
Mice
Mice, Obese
Pancreas
Plasma
Adenosine Monophosphate
Dipeptidyl Peptidase 4
GTP-Binding Proteins
Glucagon-Like Peptide 1
Glucose
Insulin