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Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators.

著者 Fang Y , Zhang S , Wu W , Liu Y , Yang J , Li Y , Li M , Dong H , Jin Y , Liu R , Yang Z
Bioorg Chem.2019 Oct 22 ; ():103390.
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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 (EC = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC 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.
PMID: 31662212 [PubMed - as supplied by publisher]
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