Design and synthesis of potent PAR-1 antagonists based on vorapaxar

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127046. doi: 10.1016/j.bmcl.2020.127046. Epub 2020 Feb 17.

Abstract

A series of novel vorapaxar analogues with different amino substitutes at the C-7, C-9a and aromatic substitutes at the C-4 position were designed, synthesized, and evaluated for their inhibitory activity to PAR-1. Several compounds showed good potency in antagonist activity based on the intracellular calcium mobilization assay and excellent pharmacokinetics profile in rats. Among these analogues, 3d exhibited excellent PAR-1 inhibitory activity (IC50 = 0.18 μM) and the lower ability to cross the blood-brain barrier compared with vorapaxar (IC50 = 0.25 μM). Compound 3d has the potential to be developed as a new generation of PAR-1 antagonists with a better therapeutic window.

Keywords: Antiplatelet; PAR-1 antagonists; Structure-activity relationships; Vorapaxar analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Lactones / chemical synthesis
  • Lactones / chemistry
  • Lactones / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptor, PAR-1 / antagonists & inhibitors*
  • Receptor, PAR-1 / metabolism
  • Structure-Activity Relationship

Substances

  • Lactones
  • Pyridines
  • Receptor, PAR-1
  • vorapaxar