S309: sustained inhibition of platelet activity and thrombosis via iv and oral administration of cs585

Background: Uncontrolled platelet activation leads to the formation of occlusive thrombi resulting in myocardial infarction, stroke, VTE, and critical limb ischemia. There remains an unmet need for more efficacious anti-thrombotics that have sustainability in the blood. Our group recently identified a novel oxidized lipid in the blood that not only inhibits platelet function and thrombosis through activation of the prostacyclin (IP) receptor, but is both IV and orally available and exhibits a sustained inhibition of clot formation and thrombosis in vivo. Aims: Develop an antiplatelet drug, CS585, that is available by IV or oral administration and elicits an effective and sustained inhibition of platelet function and thrombosis in vivo. Methods: Using mouse thrombosis models, we assessed the ability of CS585 to induce a sustained inhibition of platelet activation and thrombosis following a one-time IV or oral administration. Thrombosis was assessed in real-time using antibody-labelled platelet and fibrin at multiple times following administration. Platelet accumulation and thrombosis were assessed using in vivo intravital confocal microscopy. Results:In vivo inhibition of injury-induced thrombosis in the cremaster arterioles by CS585 was demonstrated by measuring fibrin and platelet clot formation, stability, and accumulation at the site vessel injury. Imaging was conducted at various time points following CS585 administered either IV or by oral gavage. CS585 was observed to inhibit platelet accumulation but not fibrin formation through both routes of administration. Inhibition of clot formation was observed by IV administration as well as by oral gavage for the 18 hours tested in this study. Further, inhibition by oral gavage showed inhibition of platelet clot formation at the site of injury, dose-dependent, with as little as 1 mg/kg dosing of CS585. Summary/Conclusion: We have shown for the first time that CS585, a novel compound targeting and activating the IP receptor, inhibits in vivo platelet activation and thrombosis for at least 18 hours post administration. CS585 was shown to exhibit this prolonged inhibition of thrombosis when administered either through IV or by oral gavage. This discovery supports CS585 as a viable and new approach for prolonged prevention of platelet activation and thrombosis and potential protection from myocardial infarction, stroke, VTE, and critical limb ischemia.Figure: CS585 dose-dependently inhibits laser-induced thrombosis. Platelet accumulation (green) and fibrin formation (red). CS585 dosed in animals orally 0.5-6 mg/kg prior to injury. Keywords: Arterial thrombosis, Anti-platelet therapies, Antithrombotic therapy