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.
Wengen Wu  1 ,  Yuxin Liu ,  Lawrence J Milo Jr ,  Ying Shu ,  Peng Zhao ,  Youhua Li ,  Iwona Woznica ,  Gengli Yu ,  David G Sanford ,  Yuhong Zhou ,  Sarah E Poplawski ,  Beth A Connolly ,  James L Sudmeier ,  William W Bachovchin ,  Jack H Lai
Affiliations
  • 1. Tufts University School of Medicine, Department of Biochemistry, 136 Harrison Ave., Boston, MA 02111, United States.
PMID: 22853995 DOI: 10.1016/j.bmcl.2012.07.033
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.