Pharmacological characterization of a novel factor Xa inhibitor, FXV673
| Autor: | Charles J Kasiewski, Susan Morgan, Ross G. Bentley, Robert J. Leadley, Mark H Perrone, Jeffery Bostwick, Karen Brown, Dennis Colussi, Dunwiddie Christopher T, Yong Gong, Valeria Chu, Alison Zulli, Kevin Richard Guertin, Jingbo Gao, Pauls Henry W |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Serine Proteinase Inhibitors
medicine.drug_mechanism_of_action Plasmin Pyridines Factor Xa Inhibitor Cyclic N-Oxides Thrombin Dogs Fibrinolytic Agents Prothrombinase medicine Animals Humans Platelet Blood coagulation test medicine.diagnostic_test Dose-Response Relationship Drug Chemistry Factor V Membranes Artificial Thrombosis Hematology Haplorhini Molecular biology Rats Disease Models Animal Kinetics Carotid Arteries Biochemistry Factor Xa Blood Coagulation Tests Jugular Veins Protein C Partial thromboplastin time medicine.drug Factor Xa Inhibitors |
| Zdroj: | Thrombosis research. 103(4) |
| ISSN: | 0049-3848 |
| Popis: | FXV673 is a novel, potent, and selective factor Xa (FXa) inhibitor. FXV673 inhibited human, dog, and rabbit FXa with a K(i) of 0.52, 1.41, and 0.27 nM, respectively. FXV673 also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C (aPC), plasmin, and tissue-plasminogen activator (t-PA). FXV673 prolonged plasma activated partial thromboplastin time (APTT) and prothrombin time (PT) in a dose-dependent fashion. In the APTT assays, the concentrations (microM) required for doubling coagulation time were 0.41 (human), 0.65 (monkey), 1.12 (dog), 0.25 (rabbit), and 0.80 (rat). The concentrations (microM) required in the PT assays were 1.1 (human), 1.32 (monkey), 2.31 (dog), 0.92 (rabbit), and 1.69 (rat). A coupled-enzyme assay was performed to measure thrombin activity following prothrombinase conversion of prothrombin to thrombin. FXV673 showed IC(50)s of 1.38 and 2.55 nM, respectively, when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or fresh platelets were used as the phospholipid source for prothrombinase complex formation. It was demonstrated that FXV673 could inhibit further thrombin generation in the prothrombinase complex using PS/PC liposomes. FXV673 dose-dependently prolonged the time to vessel occlusion and inhibited thrombus formation in well-characterized canine models of thrombosis. Interspecies extrapolation (approximately 2.5-fold higher sensitivity for FXa inhibition in human than in dog) suggested that 100 ng/ml of FXV673 would be an effective plasma concentration for clinical studies. Currently FXV673 is undergoing clinical studies to be developed as an antithrombotic agent. |
| Databáze: | OpenAIRE |
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