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Research ArticleCARDIOVASCULAR

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Claudia K. Derian, Bruce P. Damiano, Michael F. Addo, Andrew L. Darrow, Michael R. D'Andrea, Mark Nedelman, Han-Cheng Zhang, Bruce E. Maryanoff and Patricia Andrade-Gordon
Journal of Pharmacology and Experimental Therapeutics February 2003, 304 (2) 855-861; DOI: https://doi.org/10.1124/jpet.102.042663
Claudia K. Derian
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Bruce P. Damiano
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Michael F. Addo
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Andrew L. Darrow
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Michael R. D'Andrea
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Mark Nedelman
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Han-Cheng Zhang
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Bruce E. Maryanoff
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Patricia Andrade-Gordon
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This article has a correction. Please see:

  • Correction to “Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates” - April 01, 2003

Abstract

Although it is well recognized that human platelet responses to α-thrombin are mediated by the protease-activated receptors PAR-1 and PAR-4, their role and relative importance in platelet-dependent human disease has not yet been elucidated. Because the expression profile of PARs in platelets from nonprimates differs from humans, we used cynomolgus monkeys to evaluate the role of PAR-1 in thrombosis. Based on reverse transcription-polymerase chain reaction, PAR expression in platelets from cynomolgus monkeys consisted primarily of PAR-1 and PAR-4, thereby mirroring the profile of human platelets. We probed the role of PAR-1 in a primate model of vascular injury-induced thrombosis with the selective PAR-1 antagonist (αS)-N-[(1S)-3-amino-1-[[(phenylmethyl)amino]carbonyl]propyl]-α-[[[[[1-(2,6-dichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indazol-6-yl]amino]carbonyl]amino]-3,4-difluorobenzenepropanamide (RWJ-58259). After pretreatment with RWJ-58259 or vehicle, both carotid arteries of anesthetized monkeys were electrolytically injured and blood flow was monitored for 60 min. Time to occlusion was significantly extended after RWJ-58259 administration (27 ± 3 to 53 ± 8 min; p < 0.048). Vessels from three of the five treated animals remained patent. Ex vivo platelet aggregation measurements indicated complete PAR-1 inhibition, as well as an operational PAR-4 response. Immunohistochemical staining of mural thrombi with antibodies to the platelet marker CD61 and fibrinogen indicated that RWJ-58259 significantly reduced thrombus platelet deposition. Drug treatment had no effect on key hematological or coagulation parameters. Our results provide direct evidence that PAR-1 is the primary receptor that mediates α-thrombin's prothrombotic actions in primates and suggest that PAR-1 antagonists may have potential for the treatment of thrombotic disorders in humans.

Footnotes

  • DOI: 10.1124/jpet.102.042663

  • Abbreviations:
    PAR
    protease-activated receptor
    PCR
    polymerase chain reaction
    PRP
    platelet-rich plasma
    RT
    reverse transcriptase
    RWJ-58259
    (αS)-N-[(1S)-3-amino-1-[[(phenylmethyl)amino]carbonyl]propyl]-α-[[[[[1-(2,6-dichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indazol-6-yl]amino]carbonyl]amino]-3,4-difluorobenzenepropanamide
    • Received August 12, 2002.
    • Accepted October 24, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 2
1 Feb 2003
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Research ArticleCARDIOVASCULAR

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Claudia K. Derian, Bruce P. Damiano, Michael F. Addo, Andrew L. Darrow, Michael R. D'Andrea, Mark Nedelman, Han-Cheng Zhang, Bruce E. Maryanoff and Patricia Andrade-Gordon
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 855-861; DOI: https://doi.org/10.1124/jpet.102.042663

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Research ArticleCARDIOVASCULAR

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Claudia K. Derian, Bruce P. Damiano, Michael F. Addo, Andrew L. Darrow, Michael R. D'Andrea, Mark Nedelman, Han-Cheng Zhang, Bruce E. Maryanoff and Patricia Andrade-Gordon
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 855-861; DOI: https://doi.org/10.1124/jpet.102.042663
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