Pharmacological Characterization of a Novel Factor Xa Inhibitor, FXV673

• Published in: Thrombosis research Vol. 103; no. 4; pp. 309 - 324
• Main Authors: Chu, Valeria, Brown, Karen, Colussi, Dennis, Gao, Jingbo, Bostwick, Jeffery, Kasiewski, Charles, Bentley, Ross, Morgan, Susan, Guertin, Kevin, Pauls, Henry W, Gong, Yong, Zulli, Alison, Perrone, Mark H, Dunwiddie, Christopher T, Leadley, Robert J
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Ltd 15.08.2001; Elsevier Science
• Subjects: Animals; Anticoagulant; Antithrombotic; Biological and medical sciences; Blood Coagulation Tests; Blood. Blood coagulation. Reticuloendothelial system; Canine arterial venous thrombosis models; Carotid Arteries; Cyclic N-Oxides - administration & dosage; Cyclic N-Oxides - pharmacology; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Factor V - antagonists & inhibitors; Factor Xa; Factor Xa inhibitor; Factor Xa Inhibitors; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - pharmacology; FXV673; Haplorhini; Humans; Jugular Veins; Kinetics; Medical sciences; Membranes, Artificial; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - pharmacology; Rats; Serine Proteinase Inhibitors - administration & dosage; Serine Proteinase Inhibitors - pharmacology; Thrombosis - drug therapy; APTT; PT; Antithrombotic; Factor Xa inhibitor; Anticoagulant; Canine arterial venous thrombosis models; FXV673; Serine endopeptidases; Enzyme; Cardiovascular disease; Coagulation Factor Xa; Thrombosis; Biological activity; Vascular disease; Prevention; Peptidases; Treatment; Hydrolases; Inhibitor; Pharmacokinetics
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/S0049-3848(01)00328-0

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 (μM) required for doubling coagulation time were 0.41 (human), 0.65 (monkey), 1.12 (dog), 0.25 (rabbit), and 0.80 (rat). The concentrations (μM) 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 50s 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 (∼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.