Herbert J M, Bernat A, Dol F, Hérault J P, Crépon B, Lormeau J C
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
J Pharmacol Exp Ther. 1996 Mar;276(3):1030-8.
DX 9065A is the first member of a newly developed series of synthetic and selective inhibitors of factor Xa. DX 9065A inhibited in a dose-dependent manner human factor Xa with K iota value of 3.1 +/- 0.5 nM. Steady-state studies revealed that DX 9065A was a competitive inhibitor of factor Xa. DX 9065A inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway in vitro and in vivo. After i.v. injection to rabbits, DX 9065A displayed prolonged anti-factor Xa activity and inhibition of thrombin generation. Pretreatment of mice with DX 9065A dose-dependently improved the survival rate of mice injected with a lethal dose of tissue factor (ED50 = 1.1 +/- 0.2 mg/kg). After p.o. administration, DX 9065A caused a reduction in tissue factor-induced mortality of mice with ED50 value of 56 +/- 7 mg/kg. When given i.v. to rats, DX 9065A exhibited a dose-dependent antithrombotic effect against factor Xa + stasis-induced venous thrombosis (ED50 = 1.2 +/- 0.7 mg/kg i.v.), but also in an arteriovenous shunt thrombosis model (ED50 = 8.1 +/- 3.5 mg/kg i.v.) without affecting bleeding time significantly. Similar effects were obtained after s.c. or p.o. administration. In rabbits, after i.v., s.c. or p.o. administration, DX 9065A inhibited stasis-induced thrombosis after injection of tissue factor with ED50 values of 0.03 +/- 0.01, 0.3 +/- 0.07 and 50.5 +/- 19 mg/kg, respectively (n = 10). DX 9065A inhibited in a dose-dependent manner endotoxin-induced venous thrombosis in the rabbit (ED50 = 0.25 +/- 0.1 mg/kg i.v.) (n = 5) and reduced the decrease in platelet number and circulating fibrinogen levels in an experimental model of tissue factor-induced disseminated intravascular coagulation. Compared to standard heparin, DX 9065A exhibited a favorable antithrombotic/bleeding ratio, therefore showing that it might be considered as a promising compound in the treatment and prevention of various thrombotic diseases.
DX 9065A是新开发的一系列合成性和选择性Xa因子抑制剂中的首个成员。DX 9065A以剂量依赖性方式抑制人Xa因子，其解离常数（Ki）值为3.1±0.5纳摩尔。稳态研究表明DX 9065A是Xa因子的竞争性抑制剂。DX 9065A在体外和体内均抑制通过外源性和内源性途径产生的凝血酶。静脉注射给兔子后，DX 9065A显示出延长的抗Xa因子活性并抑制凝血酶生成。用DX 9065A预处理小鼠可剂量依赖性地提高注射致死剂量组织因子的小鼠的存活率（半数有效剂量[ED50]=1.1±0.2毫克/千克）。口服给药后，DX 9065A使组织因子诱导的小鼠死亡率降低，ED50值为56±7毫克/千克。静脉注射给大鼠时，DX 9065A对Xa因子+血流淤滞诱导的静脉血栓形成表现出剂量依赖性抗血栓作用（静脉注射ED50=1.2±0.7毫克/千克），在动静脉分流血栓形成模型中也有此作用（静脉注射ED50=8.1±3.5毫克/千克），且对出血时间无显著影响。皮下或口服给药后也获得类似效果。在兔子中，静脉注射、皮下注射或口服给药后，DX 9065A抑制注射组织因子后血流淤滞诱导的血栓形成，ED50值分别为0.03±0.01、0.3±0.07和50.5±19毫克/千克（n=10）。DX 9065A以剂量依赖性方式抑制兔子内毒素诱导的静脉血栓形成（静脉注射ED50=0.25±0.1毫克/千克）（n=5），并在组织因子诱导的弥散性血管内凝血实验模型中减少血小板数量和循环纤维蛋白原水平的降低。与标准肝素相比，DX 9065A表现出良好的抗血栓形成/出血比率，因此表明它可能被视为治疗和预防各种血栓性疾病的有前景的化合物。
