The Eicosanoid Analogue Cs585 Represents A First-in-class In Prevention Of Platelet Activation And Thrombosis Through Direct Activation Of The Prostacyclin Receptor

Cardiovascular disease remains the primary cause of morbidity and mortality today and impinges on a number of organ systems including the vessels, heart, lungs, and brain with thrombotic complications. While platelet activation is critical for maintaining hemostasis and preventing leakage of blood cells from the vessel to extravascular compartments, the platelet clotting system is highly regulated to prevent an occlusive thrombus that deprives key organ systems of oxygen. To this end, the platelet remains a primary target for regulation of hemostasis and thrombosis. While current pharmacological regulation of the platelet has significantly reduced mortality, admittedly to a certain price of bleedings, there has been a paucity of successful targeting of platelet reactivity beyond cyclooxygenase-1, P2Y 12 receptor, integrin αIIbβ3, and phosphodiesterase. Recently, an oxidized lipid produced in the blood that limits platelet activation through activation of the prostacyclin receptor has been identified. Here, we demonstrate for the first time, a novel analogue of the oxidized lipid, known as CS585. CS585 is shown to potently target the prostacyclin receptor on the human platelet resulting in a highly selective and effective mechanism for prevention of thrombosis. Further, CS585 is shown to function in human whole blood ex vivo and in prevention both small and large vessel thrombosis in mouse models. Finally, we demonstrate that CS585 does not perturb coagulation or increase the risk for bleeding. Hence, we have developed a novel small molecule agonist that is selective for the prostacyclin receptor, stable in human and mouse blood, is effective in prevention of unwanted platelet-mediated thrombosis and doesn’t alter hemostasis. This discovery represents a new validated target in the treatment of thrombotic diseases in the blood and vessel without the observed risks of bleeding and off-target activation of other prostaglandin receptors.