Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema: part 2

Bioorg Med Chem. 2013 May 1;21(9):2478-94. doi: 10.1016/j.bmc.2013.02.048. Epub 2013 Mar 14.

Abstract

Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although our previous compound 1 showed potent VAP-1 inhibitory activity, the activity differed between humans and rats. This issue was overcome by a hybrid design using human VAP-1 specific inhibitor 2, which was found by high-throughput screening (HTS), a docking study of a human VAP-1 homology model, and an analysis of sequence information for humans and rats. As a result, we identified compound 35c, which showed strong VAP-1 inhibitory activity (human IC(50) of 20 nM; rat IC(50) of 72 nM) and significant inhibitory effects in the ex vivo test.

MeSH terms

  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
  • Amine Oxidase (Copper-Containing) / blood
  • Animals
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Cell Adhesion Molecules / blood
  • Diabetic Retinopathy / drug therapy*
  • Dose-Response Relationship, Drug
  • Humans
  • Macular Edema / drug therapy*
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Cell Adhesion Molecules
  • Thiazoles
  • AOC3 protein, human
  • Amine Oxidase (Copper-Containing)
  • vascular adhesion protein-1, rat