DX-9065A, A NOVEL, SYNTHETIC, SELECTIVE AND ORALLY-ACTIVE INHIBITOR OF FACTOR XA - IN-VITRO AND IN-VIVO STUDIES

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-de pendent manner human factor Xa with a K-i value of 3.1 +/- 0.5 nM. Ste ady-state studies revealed that DX 9065A was a competitive inhibitor o f 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 acti vity 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 (ED(50) = 1.1 +/- 0.2 mg/kg). Afte r p.o. administration, DX 9065A caused a reduction in tissue factor-in duced mortality of mice with an ED(50) value of 56 +/- 7 mg/kg. When g iven i.v. to rats, DX 9065A exhibited a dose-dependent antithrombotic effect against factor Xa + stasis-induced venous thrombosis (ED(50) = 1.2 +/- 0.7 mg/kg i.v.), but also in an arteriovenous shunt thrombosis model (ED(50) = 8.1 +/- 3.5 mg/kg i.v.) without affecting bleeding ti me significantly. Similar effects were obtained after s.c. or p.o. adm inistration. In rabbits, after i.v., s.c. or p.o, administration, DX 9 065A inhibited stasis-induced thrombosis after injection of tissue fac tor with ED(50) 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 m anner endotoxin-induced venous thrombosis in the rabbit (ED(50) = 0.25 +/- 0.1 mg/kg i.v.) (n = 5) and reduced the decrease in platelet numb er and circulating fibrinogen levels in an experimental model of tissu e factor-induced disseminated intravascular coagulation. Compared to s tandard heparin, DX 9065A exhibited a favorable antithrombotic/bleedin g ratio, therefore showing that it might be considered as a promising compound in the treatment and prevention of various thrombotic disease s.