Design, synthesis and biological evaluation of glycolamide, glycinamide, and β-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors.

Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N'-disubstituted glycinamide, β-amino ester, and β-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of β-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and β-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, β-amino ester 5n and β-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π-π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.