4-Substituted boro-proline dipeptides: synthesis, characterization, and dipeptidyl peptidase IV, 8, and 9 activities

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5536-40. doi: 10.1016/j.bmcl.2012.07.033. Epub 2012 Jul 14.

Abstract

The boroProline-based dipeptidyl boronic acids were among the first DPP-IV inhibitors identified, and remain the most potent known. We introduced various substitutions at the 4-position of the boroProline ring regioselectively and stereoselectively, and incorporated these aminoboronic acids into a series of 4-substituted boroPro-based dipeptides. Among these dipeptidyl boronic acids, Arg-(4S)-boroHyp (4q) was the most potent inhibitor of DPP-IV, DPP8 and DPP9, while (4S)-Hyp-(4R)-boroHyp (4o) exhibited the most selectivity for DPP-IV over DPP8 and DPP9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boronic Acids / chemical synthesis
  • Boronic Acids / chemistry*
  • Boronic Acids / pharmacology*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / enzymology
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Proline / chemical synthesis
  • Proline / chemistry*
  • Proline / pharmacology*

Substances

  • Boronic Acids
  • Dipeptides
  • Proline
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases