Gamma-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors

J Med Chem. 2004 May 20;47(11):2906-16. doi: 10.1021/jm031122f.


Using 1-[(S)-2,4-diaminobutanoyl]piperidine as lead compound, we developed a large series of highly potent and selective dipeptidyl peptidase II (DPP II) inhibitors. gamma-Amino substitution with arylalkyl groups, for example, a 2-chlorobenzyl moiety, resulted in a DPP II inhibitor with an IC(50) = 0.23 nM and a high selectivity toward DPP IV (IC(50) = 345 microM). Furthermore, it was shown that the basicity of the gamma-amino is important and that alpha-amino substitution is not favorable. Piperidine-2-nitriles did not show an increase in potency but rather reduced the selectivity. Introduction of a 4-methyl or a 3-fluorine on piperidine improved selectivity and preserved the high potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / chemistry
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Structure-Activity Relationship


  • Piperidines
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • dipeptidyl peptidase II
  • Dipeptidyl Peptidase 4