act-246475 and Thrombosis

Platelet P2Y. Selatogrel, formerly known as ACT-246475, is a novel, potent, reversible, and selective non-thienopyridine antagonist of the P2Y. Advantages of subcutaneous administration of selatogrel are fast onset of action, easy administration and the fecal excretion not requiring dose adjustment based on renal function. These characteristics may translate into an advantage in the peri-procedural setting and in emergency and/or unconscious patients. Selatogrel may represent a viable alternative to intravenous P2Y

Topics: Acute Coronary Syndrome; Animals; Drug Development; Humans; Injections, Subcutaneous; Organophosphonates; Percutaneous Coronary Intervention; Purinergic P2Y Receptor Antagonists; Pyrimidines; Thrombosis

Selatogrel is a reversible antagonist of the P2Y12 receptor. In rat thrombosis/haemostasis models, selatogrel was associated with lower blood loss than clopidogrel or ticagrelor at equivalent anti-thrombotic effect.. We sought to elucidate the mechanism underlying the observed differences in blood loss, using real-time intravital microscopy in mouse.. Selatogrel, ticagrelor and clopidogrel dose-dependently inhibited laser-induced platelet thrombus formation. At maximal antithrombotic effect, only small mural platelets aggregates, corresponding to hemostatic seals, were present. The phenotype of these hemostatic seals was dependent on the type of P2Y12 receptor antagonist. In the presence of clopidogrel and ticagrelor, detachment of platelets from the hemostatic seals was increased, indicative of reduced stability. In contrast, in the presence of selatogrel, platelet detachment was not increased. Moreover, equivalent antithrombotic dosing regimens of ticagrelor and clopidogrel reduced laser-induced calcium mobilization in the endothelium, restricted neutrophil adhesion and subsequent fibrin formation and thus reduced fibrin-mediated stabilization of the hemostatic seals. The effects of ticagrelor were also observed in P2Y12 receptor deficient mice, indicating that the effects are off-target and independent of the P2Y12 receptor. In contrast, selatogrel did not interfere with these elements of haemostasis in wild-type or in P2Y12 receptor deficient mice.. In the presence of selatogrel the stability of hemostatic seals was unperturbed, translating to an improved blood loss profile. Our data suggest that the mechanism underlying the differences in blood loss profiles of P2Y12 receptor antagonists is by off-target interference with endothelial activation, neutrophil function and thus, fibrin-mediated stabilization of haemostatic seals.

Topics: Animals; Blood Platelets; Hemostatics; Mice; Organophosphonates; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrimidines; Rats; Receptors, Purinergic P2Y12; Thrombosis