Savi P, Badorc A, Lalé A, Bordes M F, Bornia J, Labouret C, Bernat A, de Cointet P, Hoffmann P, Maffrand J P, Herbert J M
Sanofi Recherche, Haemobiology Research Department, Toulouse, France.
Thromb Haemost. 1998 Sep;80(3):469-76.
The aim of this study was to describe the pharmacological properties of SR 121787, a new antiaggregating drug which is metabolized in vivo into SR 121566, a potent non-peptide antagonist of Gp IIb/IIIa. In vitro, SR 121566 antagonized the binding of [125I]-fibrinogen (IC50 = 19.8+/-6.3 nM) and of [125I]-L-692,884, an RGD-containing peptide (IC50 = 291+/-96 nM) to activated human platelets. SR 121566 inhibited the aggregation of human platelets induced by ADP, collagen, thrombin, arachidonic acid and PAF at concentrations lower than 0.1 microM. Adhesion of human platelets to adhesive proteins was inhibited by SR 121566 (IC50 = 40.3+/-2.5 nM) only when Gp IIb/IIIa and fibrinogen were involved. No effect was found with regard to other adhesive proteins and/or other integrins. SR 121787 demonstrated a potent and sustained antiaggregating effect when administered intravenously to baboons at a dose 50 microg/kg, and eight hours after the administration of 100 microg/kg, ADP-induced aggregation was still strongly inhibited (more than 80%). A single oral administration of 2 mg/kg of SR 121787 produced a nearly complete inhibition of platelet aggregation for up to 8 h (ED50 at 8 h = 193+/-20 microg/kg), a significant residual antiaggregating activity being still observed 24h after the administration. When administered orally to rabbits, SR 121787 exhibited a potent antiaggregating (ED50 = 2.3+/-0.3 mg/kg) and antithrombotic activity in an arterio-venous shunt thrombosis model (ED50 = 10.4+/-0.8 mg/kg). After oral and IV administration, SR 121787 was well tolerated suggesting that SR 121787, the most potent and long lasting orally active Gp IIb/IIIa antagonist described to date, is a promising antithrombotic compound.
本研究的目的是描述新型抗聚集药物SR 121787的药理学特性，该药物在体内代谢为SR 121566，一种强效的Gp IIb/IIIa非肽拮抗剂。在体外，SR 121566拮抗[125I] - 纤维蛋白原（IC50 = 19.8±6.3 nM）和[125I] - L - 692,884（一种含RGD的肽，IC50 = 291±96 nM）与活化的人血小板的结合。SR 121566在浓度低于0.1 microM时抑制ADP、胶原、凝血酶、花生四烯酸和PAF诱导的人血小板聚集。仅当涉及Gp IIb/IIIa和纤维蛋白原时，SR 121566才抑制人血小板与粘附蛋白的粘附（IC50 = 40.3±2.5 nM）。对于其他粘附蛋白和/或其他整合素未发现作用。当以50微克/千克的剂量静脉注射给狒狒时，SR 121787表现出强效且持续的抗聚集作用，在给予100微克/千克后8小时，ADP诱导的聚集仍被强烈抑制（超过80%）。单次口服2毫克/千克的SR 121787可产生长达8小时的几乎完全的血小板聚集抑制（8小时时的ED50 = 193±20微克/千克），在给药后24小时仍观察到显著的残余抗聚集活性。当口服给予兔子时，SR 121787在动静脉分流血栓形成模型中表现出强效的抗聚集（ED50 = 2.3±0.3毫克/千克）和抗血栓活性（ED50 = 10.4±0.8毫克/千克）。经口服和静脉给药后，SR 121787耐受性良好，这表明SR 121787是迄今为止描述的最有效且长效的口服活性Gp IIb/IIIa拮抗剂，是一种有前景的抗血栓化合物。
