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

• Published in: Bioorganic chemistry 2021-09, Vol.114, p.105049-105049, Article 105049
• Main Authors: Fuh, Mao-Tsu, Tseng, Ching-Chun, Li, Sin-Min, Tsai, Shuo-En, Chuang, Tsung-Jui, Lu, Chih-Hao, Yang, Ya-Chen, Tsai, Henry J., Wong, Fung Fuh
• Format: Article
• Language: English
• Subjects: 1,2,4-Triazole; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dose-Response Relationship, Drug; DPP-4 inhibitors; Drug Design; Glycinamide; Glycine - analogs & derivatives; Glycine - chemical synthesis; Glycine - chemistry; Glycine - pharmacology; Glycolamides; Glycolates - chemical synthesis; Glycolates - chemistry; Glycolates - pharmacology; Humans; Molecular Structure; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; β-amino carbonyl
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105049

Through modification of the skeleton of Sitagliptin and Vildagliptin, 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, were designed, synthesized, and inhibitory activity evaluated against the DPP-4 enzyme. 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). Docking study also revealed compounds 5n, 6d and 6p have favorable binding mode with DPP-4 enzyme. The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor. [Display omitted] •1,2,4-Triazole containing four series of linkers were designed as DPP-4 inhibitors.•Through SAR, the tendency order of DPP-4 inhibition activity: 3