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

@article{Wen2014SubstitutedIA,
  title={Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.},
  author={Wandong Wen and Summer E. Young and Matthew Thomas Duvernay and Michael L. Schulte and Kellie D. Nance and Bruce J. Melancon and Julie L. Engers and Charles W. Locuson and Michael R. Wood and John Scott Daniels and Wenjun Wu and Craig W. Lindsley and Heidi E. Hamm and Shaun R Stauffer},
  journal={Bioorganic \& medicinal chemistry letters},
  year={2014},
  volume={24 19},
  pages={
          4708-4713
        }
}
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). 
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TLDR
A series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3.5-Molecule, maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin.
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Molecular requirements involving the human platelet protease-activated receptor-4 mechanism of activation by peptide analogues of its tethered-ligand
TLDR
Conclusively, the lipophilicity, size, and aromatic nature of the residue preceding Tyr-2 are determining factors on whether a human platelet PAR-4 tethered-ligand peptide analogue will exert an agonistic or antagonistic activity.
Characterizing the interaction modes of PAR4 receptor with agonist and antagonist by molecular simulation approach
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PAR4 (Protease-Activated Receptor 4): PARticularly Important 4 Antiplatelet Therapy.
  • Xu Han, M. Nieman
  • Medicine, Chemistry
    Arteriosclerosis, thrombosis, and vascular biology
  • 2018
TLDR
The dual receptor system offers the intriguing possibility of pharmacologically fine-tuning thrombin signaling in platelets by taking advantage of the individual contributions of PAR1 and PAR4.
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