Protease-activated receptor 1 antagonists prevent platelet aggregation and adhesion without affecting thrombin time

The aim of this study was to investigate the in vitro antithrombotic effects of two PAR1 antagonists, ER121958 and SCH203099 on both SFLLR-induced platelet adhesion and aggregation and on the thrombin time in human and guinea-pig platelets. ER121958 inhibited SFLLR-induced guinea-pig and human platelet adhesion with the IC50 values of 1.73 nM and 2.91 nM, respectively and SFLLR-induced guinea-pig and human platelet aggregation with the IC50 values of 2.74 nM and 11.9 nM, respectively. Similarly, SCH203099 exhibited a non competitive profile of inhibition on both SFLLR-induced guinea-pig and human platelet adhesion with the IC50 values of 93 nM and 127 nM, respectively or SFLLR-induced guinea-pig and human platelet aggregation with the IC50 values of 1.74 μM and 2.36 μM, respectively. These two antagonists failed to prolong the thrombin time. Altogether, these results highlighted the potent anti-platelets properties of both ER121958 and SCH203099 in an in vitro model of aggregation as well as in a static model of adhesion without any effect on the last step of coagulation cascade. Moreover, this work emphasized that guinea-pig is a suitable animal model to study the role of PAR1 antagonists since the magnitude of the effects of ER121958 and SCH203099 on both SFLLR-induced platelet adhesion and aggregation were similar in both species.