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

Philippe G. Nantermet, James Barrow, George F. Lundell, Janetta M. Pellicore, Kenneth E. Rittle, MaryBeth 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

Fingerprint

Thrombin Receptors
Platelet Aggregation Inhibitors
Platelets
Thrombin
Molecules
Platelet Activation
Platelet Aggregation
Peptides
Agglomeration
Chemical activation
Lead

ASJC Scopus subject areas

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

Cite this

Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1). / Nantermet, Philippe G.; Barrow, James; Lundell, George F.; Pellicore, Janetta M.; Rittle, Kenneth E.; Young, MaryBeth; Freidinger, Roger M.; Connolly, Thomas M.; Condra, Cindra; Karczewski, Jerzy; Bednar, Rodney A.; Gaul, Stanley L.; Gould, Robert J.; Prendergast, Kris; Selnick, Harold G.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 12, No. 3, 11.02.2002, p. 319-323.

Research output: Contribution to journalArticle

Nantermet, PG, Barrow, J, Lundell, GF, Pellicore, JM, Rittle, KE, Young, M, Freidinger, RM, Connolly, TM, Condra, C, Karczewski, J, Bednar, RA, Gaul, SL, Gould, RJ, Prendergast, K & Selnick, HG 2002, 'Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)', Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 3, pp. 319-323. https://doi.org/10.1016/S0960-894X(01)00745-4
Nantermet, Philippe G. ; Barrow, James ; Lundell, George F. ; Pellicore, Janetta M. ; Rittle, Kenneth E. ; Young, MaryBeth ; Freidinger, Roger M. ; Connolly, Thomas M. ; Condra, Cindra ; Karczewski, Jerzy ; Bednar, Rodney A. ; Gaul, Stanley L. ; Gould, Robert J. ; Prendergast, Kris ; Selnick, Harold G. / Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1). In: Bioorganic and Medicinal Chemistry Letters. 2002 ; Vol. 12, No. 3. pp. 319-323.
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