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Thrombin Receptor Antagonists for the Treatment of Atherothrombosis

Therapeutic Potential of Vorapaxar and E-5555

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Abstract

Platelet activation, achieved through a variety of surface receptors and biochemical mediators, represents a key event in the pathogenesis of atherothrombosis and its clinical manifestations. The major pathways involved in platelet activation are triggered by thromboxane A2, adenosine diphosphate and thrombin, with the latter being the most potent of these agonists. Despite the effective inhibition of the first two pathways with aspirin and several generations of P2Y12 receptor antagonists, respectively, the recurrence of ischaemic events in patients with atherothrombosis remains high. In addition, there is a growing concern over the safety profile of increasingly powerful antiplatelet drugs in terms of bleeding, which has tempered expectations of newly developed compounds.

Thrombin receptor antagonists are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds may have the potential to improve ischaemic outcomes without significantly increasing the bleeding liability. Currently, two agents of this class are under clinical development: vorapaxar (previously known as SCH 530348) and E-5555. In this review we discuss this novel class of antiplatelet agents, focusing in particular on their therapeutic potential.

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. Drs Becker, Leonardi and Tricoci declare that The Duke Clinical Research Institute has received research grants for clinical trials with PAR-1 receptor antagonists. Drs Becker and Tricoci have received scientific advisory board honoraria from Merck.

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Authors and Affiliations

  1. Duke Clinical Research Institute, 2400 Pratt Street, Durham, North Carolina, 27705, USA

    Sergio Leonardi, Pierluigi Tricoci &  Richard C. Becker

  2. Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Sergio Leonardi

  3. Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA

    Pierluigi Tricoci &  Richard C. Becker

  4. Division of Hematology, Duke University School of Medicine, Durham, North Carolina, USA

    Richard C. Becker

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  1. Sergio Leonardi
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  2. Pierluigi Tricoci
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  3. Richard C. Becker
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Correspondence to Richard C. Becker.

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Leonardi, S., Tricoci, P. & Becker, R.C. Thrombin Receptor Antagonists for the Treatment of Atherothrombosis. Drugs 70, 1771–1783 (2010). https://doi.org/10.2165/11538060-000000000-00000

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