Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors

Bioorg Med Chem Lett. 2007 Jul 15;17(14):3877-9. doi: 10.1016/j.bmcl.2007.04.106. Epub 2007 May 3.

Abstract

Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.

MeSH terms

  • Dipeptidyl-Peptidase IV Inhibitors*
  • Drug Design
  • Models, Molecular
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Protease Inhibitors
  • Pyrimidines