Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides

J Med Chem. 1996 May 10;39(10):2087-94. doi: 10.1021/jm950732f.

Abstract

A series of prolineboronic acid (boroPro) containing dipeptides were synthesized and assayed for their ability to inhibit the serine protease dipeptidyl peptidase IV (DPPIV). Inhibitory activity, which requires the (R)-stereoisomer of boroPro in the P1 position, appears to tolerate a variety of L-amino acids in the P2 position. Substitution at the P2 position which is not tolerated include the D-amino acids, alpha,alpha-disubstituted amino acids, and glycine. Specificity against DPPII and proline specific endopeptidase is reported. A correlation between the ability to inhibit DPPIV in cell culture and in the human mixed lymphocyte reaction is demonstrated. A synthesis of prolineboronic acid is reported as well as conditions for generating the fully unprotected boronic acid dipeptides in either their cyclic or acyclic forms.

MeSH terms

  • Boronic Acids / chemistry*
  • Boronic Acids / pharmacology*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lymphocyte Culture Test, Mixed
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Boronic Acids
  • Enzyme Inhibitors
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases