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 IC(50) values of 1.73nM and 2.91nM, respectively and SFLLR-induced guinea-pig and human platelet aggregation with the IC(50) values of 2.74nM and 11.9nM, respectively. Similarly, SCH203099 exhibited a non competitive profile of inhibition on both SFLLR-induced guinea-pig and human platelet adhesion with the IC(50) values of 93nM and 127nM, respectively or SFLLR-induced guinea-pig and human platelet aggregation with the IC(50) values of 1.74microM and 2.36microM, 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.
Nadal-Wollbold
Florence
F
Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106 Castres cedex, France. florence.nadal_wollbold@pierre-fabre.com
Bocquet
Arnaud
A
Bourbon
Thierry
T
Létienne
Robert
R
Le Grand
Bruno
B
D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D054833:Isoindoles / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013045:Species Specificity; D013918:Thrombin Time
C550447:ER 121958; D054833:Isoindoles; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D011799:Quinazolines