Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)

Bioorg Med Chem Lett. 2002 Feb 11;12(3):319-23. doi: 10.1016/s0960-894x(01)00745-4.

Abstract

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.

MeSH terms

  • Azepines / chemical synthesis*
  • Azepines / pharmacology*
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Drug Design
  • Humans
  • In Vitro Techniques
  • Indicators and Reagents
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / pharmacology*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / pharmacology
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Platelet Activation / drug effects
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / pharmacology
  • Receptor, PAR-1
  • Receptors, Thrombin / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors

Substances

  • 5-(3-(hexahydroazepin-1-yl)propyl)(benzodioxol-5-yl)amino-3-(3,5-difluorophenyl)isoxazole
  • Azepines
  • Indicators and Reagents
  • Isoxazoles
  • Peptide Fragments
  • Piperidines
  • Platelet Aggregation Inhibitors
  • Receptor, PAR-1
  • Receptors, Thrombin
  • thrombin receptor peptide (42-55)
  • Thrombin