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.