title: Protease-activated receptor 1 antagonists prevent platelet aggregation and adhesion without affecting thrombin time.
abstract: 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.
authors.affiliation: Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106 Castres cedex, France. florence.nadal_wollbold@pierre-fabre.com
authors.forename: Florence
authors.initials: F
authors.lastname: Nadal-Wollbold
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bocquet
authors.forename: Thierry
authors.initials: T
authors.lastname: Bourbon
authors.forename: Robert
authors.initials: R
authors.lastname: Létienne
authors.forename: Bruno
authors.initials: B
authors.lastname: Le Grand
mesh_terms: 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
chemical_list: 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