Abstract
EP224283 combines in a single molecule idraparinux and tirofiban, which allows obtaining a predictable and sustained antiplatelet effect through the transfer of the pharmacokinetics properties of idraparinux to the anti-αIIbβ3 antagonist. The activity can be instantaneously neutralized by injection of avidin, a specific antidote. We have tested the effects of this new profile anticoagulant in various thrombosis models. The antithrombotic effect of EP224283 was compared with those of the parent compounds used alone or in association at doses achieving low to moderate inhibition of platelet aggregation ex vivo. In a model of systemic thromboembolism independent of thrombin generation, tirofiban and EP224283 had similar effects at equimolar doses. On the other hand, EP224283 was more potent than tirofiban or idraparinux under thrombin-dependent conditions. In a ferric chloride-induced thrombosis model, EP224283 was more potent than either parent compound or their combination. Similar results were obtained after atherosclerotic plaque rupture in ApoE(−/−) mice. Thus, the dual action of EP224283 exceeds that of the parent compounds used in combination. A possible explanation is that EP224283 could concentrate antithrombin inside the thrombus by binding to αIIbβ3 through the tirofiban moiety, as shown by immunolabeling of the occluded vessel. No prolongation of the bleeding time was observed at doses achieving strong antithrombotic effects, suggesting that low to moderate αIIbβ3 inhibition combined with factor Xa inhibition minimizes the bleeding risk. The favorable antithrombotic profile of EP224283 together with its possible neutralization by avidin makes it an interesting drug candidate for the treatment and prevention of acute ischemic events.
Footnotes
This work was supported by the Global Immersion Programme Biovalley, within the framework of the Horus Project, the Institut National de la Santé et de la Recherche Médicale, l'Etablissement Français du Sang, the Association de Recherche et Développement en Médecine et Santé Publique, the Fondation de France [Grant 2007001964], and the Agence Nationale de la Recherche [Grant ANR-06-PHYSIO-036-01]. B.H. was the recipient of a “contrat d'interface” between the l'Etablissement Français du Sang and Institut National de la Santé et de la Recherche Médicale.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.181321.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- FXa
- factor Xa
- PAR-4
- proteinase-activated receptor 4
- FeCl3
- ferric chloride
- TF
- tissue factor
- DIOC6
- 3,3′-dihexyloxacarbocyanine iodide
- ApoE(−/−)
- apolipoprotein E-deficient
- AUC
- area under curve
- AT
- antithrombin.
- Received March 4, 2011.
- Accepted April 26, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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