Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif

Bioorg Med Chem Lett. 1998 Jul 7;8(13):1649-54. doi: 10.1016/s0960-894x(98)00292-3.

Abstract

The thrombin receptor (PAR-1) is activated by alpha-thrombin to stimulate various cell types, including platelets, through the tethered-ligand sequence SFLLRN. A series of azole-based carboxamides, designed after SFLLR, were synthesized and evaluated in vitro. The compounds inhibited platelet aggregation induced by SFLLRN-NH2 or alpha-thrombin, and blocked the binding of [3H]-S-(p-F-Phe)-Har-L-Har-KY-NH2 to a CHRF membrane preparation of PAR-1. Oxazole 30 bound to PAR-1 with an IC50 of 1.6 microM, and gave IC50 values of 25 microM and 6.6 microM against alpha-thrombin- and SFLLRN-NH2-induced platelet aggregation, respectively.

MeSH terms

  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Molecular Mimicry*
  • Peptide Fragments / chemistry*
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Receptor, PAR-1
  • Receptors, Thrombin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Heterocyclic Compounds
  • Peptide Fragments
  • Platelet Aggregation Inhibitors
  • Receptor, PAR-1
  • Receptors, Thrombin
  • thrombin receptor peptide (42-47)