Discovery of potent and selective beta-homophenylalanine based dipeptidyl peptidase IV inhibitors

Bioorg Med Chem Lett. 2004 Sep 20;14(18):4759-62. doi: 10.1016/j.bmcl.2004.06.099.

Abstract

Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).

Publication types

  • Comparative Study

MeSH terms

  • Aminobutyrates / chemical synthesis*
  • Aminobutyrates / chemistry
  • Aminobutyrates / pharmacology
  • Animals
  • Biological Availability
  • Dipeptidyl Peptidase 4 / metabolism*
  • Half-Life
  • Methylation
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Aminobutyrates
  • Protease Inhibitors
  • Thiazoles
  • 2-amino-4-phenylbutyric acid
  • Dipeptidyl Peptidase 4