Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activity

被引:19
作者
Vogel, GMT
Meuleman, DG
Van Dinther, TG
Buijsman, R
Princen, AWM
Smit, MJ
机构
[1] NV Organon, Dept Pharmacol, NL-5340 BH Oss, Netherlands
[2] NV Organon, Sci Dev Grp, NL-5340 BH Oss, Netherlands
关键词
direct thrombin and AT-mediated factor Xa inhibition; thrombolysis;
D O I
10.1046/j.1538-7836.2003.00351.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org-42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man.
引用
收藏
页码:1945 / 1954
页数:10
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