Pre-clinical pharmacological profile of the novel glycoconjugate Org 36764with both factor Xa and thrombin (IIa) inhibitory activities

Org 36764. is an antithrombin III (AT) and thrombin binding carbohydrate, w hich accelerates the inactivation of both factor Xa and thrombin by AT. It displays in buffer an anti-Xa and anti-thrombin activity of 415 and 2 U/mg, respectively, compared to 172 and 114 U/mg, respectively, for unfractionat ed heparin (UFH). Org 36764 does not cross-react with HIT (heparin induced thrombocytopenia) antibodies and is not neutralised by PF4. In experimental models in rats, on a molar basis, Org 36764 was more active than the penta saccharide SanOrg 34006 (= AT binding domain of Org 36764) in arterial thro mbosis, but both were equally active in venous thrombosis. In arterial thro mbosis following endothelial damage by ferric chloride, Og 36764 was more a ctive than the LMW heparin enoxaparin and SanOrg 34006 and similar active t o UFH. At AT saturating doses the bleeding enhancement was not more than 3. 5 times the control value. Org 36764 was more active in suppressing in vivo thrombus formation on stents than UFH, SanOrg 34006 or a combination of ti clopidine and aspirin. The results indicate that the novel drug Org 36764 i s a drug with antithrombotic potential against venous and arterial thrombos is.