Synthesis and potent inhibitory activities of carboxybenzyl-substituted 8-(3-(R)-aminopiperidin-1-yl)-7-(2-chloro/cyanobenzyl)-3-methyl-3,7-dihydro-purine-2,6-diones as dipeptidyl peptidase IV (DPP-IV) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2015-05, Vol.25 (9), p.1872-1875
• Main Authors: Mo, Di-Wei, Dong, Shuai, Sun, Haiyan, Chen, Jia-Sheng, Pang, Jian-Xin, Xi, Bao-Min, Chen, Wen-Hua
• Format: Article
• Language: English
• Subjects: Benzyl Compounds - chemical synthesis; Benzyl Compounds - chemistry; Benzyl Compounds - pharmacology; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; Molecular Structure; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.03.048

Fourteen 3-methyl-3,7-dihydro-purine-2,6-dione derivatives 1-14 bearing carboxybenzyl and 2-chloro/cyanobenzyl groups at the N-1 and N-7 positions, respectively, were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors. These compounds were characterized on the basis of NMR ((1)H and (13)C) and ESI MS data. In vitro bioassay indicates that most of these compounds showed moderate to good inhibitory activities against DPP-IV. Among them, compound 13 (IC50=36 nM) exhibited comparable activity with a positive control, Sitagliptin (IC50=16 nM). In addition, the structure-activity relationship of these compounds is also briefly discussed.