Abstract Body (Do not enter title and authors here): The formation of occlusive thrombi resulting in myocardial infarction or stroke present a significant challenge for the healthcare community. Activation of the prostacyclin (IP) receptor has been shown to decrease platelet reactivity, however current IP agonists lack a sustained effect in the blood. We have developed CS585, an IP receptor agonist with sustained anti-thrombotic effects in the blood, which could represent a novel prevention strategy in targeting thrombosis. We sought to assess the anti-thrombotic efficacy and pharmacodynamic stability of IP agonists CS585, iloprost and selexipag, in both ex vivo and in vivo models.

We evaluated the timeframe of effect of CS585, iloprost, and selexipag in mice following a single IV dose. Inhibition of thrombus formation was measured ex vivo in whole blood under arterial shear rates. In vivo, CS585, iloprost, or selexipag, were administered prior to labeling of platelets and fibrin. Thrombus formation at the site of injury was measured using the cremaster arteriole injury thrombosis assay.

CS585 administered to mice prior to blood draw decreases platelet adhesion and blood clot formation under arterial shear conditions. These effects are observed up to 24 hours post-administration; however, the effects of iloprost and selexipag return to pre-treatment levels by 24 hours. In vivo, mice administered iloprost or selexipag demonstrated a decrease in platelet accumulation and fibrin formation, however the effects were abrogated post-administration by 10 minutes and 4 hours, respectively. Administration of CS585, however, demonstrated sustained inhibition of thrombus formation at the site of injury, with inhibitory effects observed at 18 hours post-administration.

We have used both in vivo and ex vivo models to demonstrate the anti-thrombotic efficacy of IP receptor agonists. Our results suggest that CS585, a novel IP receptor agonist, sustainably inhibits platelet activation and clot formation for extended periods, in contrast to existing alternatives. This demonstrates a significant improvement in the pharmacodynamic effects of IP receptor agonists in the blood, highlighting CS585 as a novel anti-platelet therapeutic with the potential to treat thrombotic diseases.