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

Bioorg Med Chem Lett. 2015 May 1;25(9):1872-5. doi: 10.1016/j.bmcl.2015.03.048. Epub 2015 Mar 24.

Abstract

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.

Keywords: 3-Methyl-3,7-dihydro-purine-2,6-dione; Diabetes; Dipeptidyl peptidase IV inhibitor; Inhibitory activity; Synthesis.

MeSH terms

  • 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

Substances

  • Benzyl Compounds
  • Dipeptidyl-Peptidase IV Inhibitors
  • Purines
  • Dipeptidyl Peptidase 4