Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354

Bioorg Med Chem Lett. 2014 Oct 1;24(19):4708-4713. doi: 10.1016/j.bmcl.2014.08.021. Epub 2014 Aug 15.


Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM).

Keywords: ML354; PAR-4 antagonist; Protease activated receptor 4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship


  • Apoptosis Regulatory Proteins
  • Indoles
  • VU0099704
  • prostate apoptosis response-4 protein