The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6340-5. doi: 10.1016/j.bmcl.2009.09.078. Epub 2009 Sep 27.

Abstract

For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.

MeSH terms

  • Amides / antagonists & inhibitors
  • Amides / chemistry*
  • Aminobutyrates / chemistry*
  • Caco-2 Cells
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
  • Drug Design
  • Humans
  • Hypoglycemic Agents / antagonists & inhibitors
  • Hypoglycemic Agents / therapeutic use
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Sodium Channels / metabolism
  • Structure-Activity Relationship*

Substances

  • Amides
  • Aminobutyrates
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Protease Inhibitors
  • Sodium Channels
  • 2-amino-4-phenylbutyric acid