The Antithrombotic Activity of EP224283, a Neutralizable Dual Factor Xa Inhibitor/Glycoprotein IIbIIIa Antagonist, Exceeds That of the Coadministered Parent Compounds

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-␣IIb␤3 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(Ϫ/Ϫ) 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 ␣IIb␤3 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 ␣IIb␤3 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.

Platelets are dispensable for antibody‐mediated transfusion‐related acute lung injury in the mouse

“…In agreement with our observations, administration of aspirin has been reported to be unable to protect critically ill patients against TRALI . Finally, the use of tirofiban to inhibit GPIIbIIIa in mice appears to be rather inadequate , owing to its known very short half‐life and poor efficacy in mice in vivo . For this reason, we preferred to use α IIb −/− platelets, considering that, under these conditions, the experiments would be more robust.…”

Heparin mimetics with anticoagulant activity

“…Structures of pentasaccharide conjugates Org39913 ( 10 ), Org42675 ( 11 ), EP217609 ( 12 ), and EP224283 ( 13 )…”

Atherosclerotic plaque injury-mediated murine thrombosis models: advantages and limitations

“…These two models are sensitive toward both antiplatelet drugs, e.g. GPIIb-IIIa antagonist eptifibatide, P2Y 12 ADP-receptor inhibitor clopidogrel and inhibitors of the common pathway of coagulation (FXa and thrombin) [18,19,23,24,46]. Yet, they display differences with respect to the role of the platelet collagen receptor GPVI, with the needle injury model being less sensitive to its inhibition as compared to the ultrasound-induced injury, which may be related to the amount of thrombin generated.…”