4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV

Bioorg Med Chem Lett. 2007 Nov 1;17(21):5806-11. doi: 10.1016/j.bmcl.2007.08.049. Epub 2007 Aug 26.

Abstract

A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.

MeSH terms

  • Administration, Oral
  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Alanine / pharmacology
  • Animals
  • Area Under Curve
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Mice
  • Models, Molecular
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Protease Inhibitors
  • Alanine