Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)

Philippe G. Nantermet, James C. Barrow, George F. Lundell, Janetta M. Pellicore, Kenneth E. Rittle, Mary Beth Young, Roger M. Freidinger, Thomas M. Connolly, Cindra Condra, Jerzy Karczewski, Rodney A. Bednar, Stanley L. Gaul, Robert J. Gould, Kris Prendergast, Harold G. Selnick

Research output: Contribution to journalArticle

Abstract

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC50s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.

Original languageEnglish (US)
Pages (from-to)319-323
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume12
Issue number3
DOIs
StatePublished - Feb 11 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Nantermet, P. G., Barrow, J. C., Lundell, G. F., Pellicore, J. M., Rittle, K. E., Young, M. B., Freidinger, R. M., Connolly, T. M., Condra, C., Karczewski, J., Bednar, R. A., Gaul, S. L., Gould, R. J., Prendergast, K., & Selnick, H. G. (2002). Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1). Bioorganic and Medicinal Chemistry Letters, 12(3), 319-323. https://doi.org/10.1016/S0960-894X(01)00745-4