Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin

Bioorg Med Chem Lett. 2007 Jun 15;17(12):3384-7. doi: 10.1016/j.bmcl.2007.03.095. Epub 2007 Apr 2.

Abstract

Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.

MeSH terms

  • Adenosine Deaminase Inhibitors*
  • Administration, Oral
  • Binding Sites
  • Crystallography, X-Ray
  • Cyclohexylamines / chemistry*
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Drug Design
  • Glycoproteins / antagonists & inhibitors*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Models, Molecular
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Sitagliptin Phosphate
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Adenosine Deaminase Inhibitors
  • Cyclohexylamines
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycoproteins
  • HIV Protease Inhibitors
  • Pyrazines
  • Triazoles
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate