The oxylipin analogue CS585 prevents platelet activation and thrombosis through activation of the prostacyclin receptor.

Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12-HETrE, produced in the platelet, was shown to limit platelet reactivity through activation of the prostacyclin receptor. Here, we demonstrate the synthesis of a novel analogue of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk for bleeding. Human platelet activation was assessd by aggregometry, flow cytometry, western blot analysis, T-TAS, microfluidic perfusion chamber, and thromboelestography. Hemostasis, thrombosis, and bleeding assays were assessed in the mouse. CS585 was shown to potently target the prostacyclin receptor on the human platelet resulting in a highly selective and effective mechanism for prevention of platelet activation. Further, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk for bleeding in the mouse model. Hence, CS585 represents a new validated target in the treatment of thrombotic diseases without the risk of bleeding and off-target activation observed with other prostaglandin receptor agonists.