Design, synthesis of novel tryptophan derivatives for antiplatelet aggregation activity based on tripeptide pENW (pGlu-Asn-Trp)

Eur J Med Chem. 2015 Sep 18:102:363-74. doi: 10.1016/j.ejmech.2015.07.016. Epub 2015 Jul 10.

Abstract

pENW, a three mer peptide derived from Agkistrodon acutus Guenther venom, has been found to be an antagonist of the GPIIb/IIIa receptor and shows antiplatelet aggregation activity. Based on pENW and a GPIIb/IIIa inhibitor Tirofiban, a series of tryptophan derivatives were designed, synthesized and evaluated for their antiplatelet aggregation activity induced by ADP. The most potent compound 87 was also tested for the bleeding time and antithrombotic activity in vivo in comparison with Tirofiban. The results indicated that 87 shows similar antiplatelet aggregation activity as Tirofiban to the aggregation of platelet induced by all of the four agonists, but has lower bleeding risk than Tirofiban, representing a promising lead compound for further study.

Keywords: Antiplatelet aggregation; Bleeding risk; GPIIb/IIIa receptor inhibitor; Tryptophan derivatives; pENW.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Pyrrolidonecarboxylic Acid / analogs & derivatives*
  • Pyrrolidonecarboxylic Acid / chemical synthesis
  • Pyrrolidonecarboxylic Acid / chemistry
  • Pyrrolidonecarboxylic Acid / pharmacology
  • Rabbits
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Platelet Aggregation Inhibitors
  • pyroglutamyl-asparagyl-tryptophan
  • Pyrrolidonecarboxylic Acid