Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile)

Biochem Pharmacol. 2005 Jul 1;70(1):134-43. doi: 10.1016/j.bcp.2005.04.009.


Vildagliptin (NVP-LAF237/(2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile) was described as a potent, selective and orally bio-available dipeptidyl-peptidase IV (DPP IV, EC inhibitor [Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, et al.1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003;46:2774-89]. Phase III clinical trials for the use of this compound in the treatment of Type 2 diabetes were started in the first quarter of 2004. In this paper, we report on (1) the kinetics of binding, (2) the type of inhibition, (3) the selectivity with respect to other peptidases, and (4) the inhibitory potency on the DPP IV catalyzed degradation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and substance P. Vildagliptin behaved as a slow-binding DPP IV inhibitor with an association rate constant of 1.4x10(5)M(-1)s(-1) and a K(i) of 17nM. It is a micromolar inhibitor for dipeptidyl-peptidase 8 and does not significantly inhibit dipeptidyl-peptidase II (EC, prolyl oligopeptidase (EC, aminopeptidase P (EC or aminopeptidase M (EC There was no evidence for substrate specific inhibition of DPP IV by Vildagliptin or for important allosteric factors affecting the inhibition constant in presence of GIP and GLP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology*
  • Binding Sites
  • Caco-2 Cells
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / drug effects*
  • Dipeptidyl Peptidase 4 / metabolism
  • Humans
  • Kinetics
  • Nitriles
  • Protease Inhibitors / pharmacology*
  • Pyrrolidines
  • Structure-Activity Relationship
  • Substrate Specificity
  • Vildagliptin


  • Nitriles
  • Protease Inhibitors
  • Pyrrolidines
  • Dipeptidyl Peptidase 4
  • Vildagliptin
  • Adamantane