期刊
BIOORGANIC CHEMISTRY
卷 94, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103390
关键词
Tetrahydropyridopyrimidine; GPR119; DPP-4; Design; Hypoglycemic activity
资金
- National Natural Science Foundation of China [81460526]
- Jiangxi Provincial Department of Science and Technology [20171BAB205103, 20181BAB215043, 20192ACB21012]
- Education Department of Jiangxi Province on Science and Technology Project Foundation [GJJ180667]
Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC50, = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 mu M. Furthermore, the blood glucose AUC(0-2h) of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.
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