Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activity
| Autor: | G.M.T. Vogel, Martin-Jan Smit, D.G. Meuleman, Rogier C. Buijsman, T. G. Van Dinther, A. W. M. Princen |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.drug_mechanism_of_action Factor Xa Inhibitor Antithrombin III Drug Evaluation Preclinical Oligosaccharides Hemorrhage Pharmacology Arginine Argatroban Thrombin Fibrinolytic Agents Prothrombinase Polysaccharides Medicine Animals Thrombolytic Therapy Rats Wistar Sulfonamides Dose-Response Relationship Drug Molecular Structure business.industry Heparin Antithrombin Thrombosis Hematology Fondaparinux Sodium Rats Fondaparinux Direct thrombin inhibitor Anesthesia Pipecolic Acids Blood Coagulation Tests Rabbits business circulatory and respiratory physiology Discovery and development of direct thrombin inhibitors medicine.drug Factor Xa Inhibitors Half-Life |
| Zdroj: | Journal of thrombosis and haemostasis : JTH. 1(9) |
| ISSN: | 1538-7933 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text