Synthesis and biological evaluation of homopiperazine derivatives with beta-aminoacyl group as dipeptidyl peptidase IV inhibitors

Bioorg Med Chem Lett. 2008 Dec 15;18(24):6525-9. doi: 10.1016/j.bmcl.2008.10.076. Epub 2008 Oct 21.


Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chemistry, Pharmaceutical / methods*
  • Crystallography, X-Ray / methods
  • Cytochrome P-450 CYP3A / chemistry
  • Diabetes Mellitus / drug therapy
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Structure
  • Piperazine
  • Piperazines / chemistry*
  • Pyrazines / pharmacology
  • Sitagliptin Phosphate
  • Structure-Activity Relationship
  • Triazoles / pharmacology


  • Dipeptidyl-Peptidase IV Inhibitors
  • Piperazines
  • Pyrazines
  • Triazoles
  • Piperazine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Sitagliptin Phosphate