Pharmacological characterization of a novel factor Xa inhibitor, FXV673.
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.
Chu
V
V
Aventis Pharmaceuticals, Mail Stop: EM-A1B, Route 202 and 206, P.O. Box 6800, Bridgewater, NJ 08807, USA. valeria.chu@aventis.com
Brown
K
K
Colussi
D
D
Gao
J
J
Bostwick
J
J
Kasiewski
C
C
Bentley
R
R
Morgan
S
S
Guertin
K
K
Pauls
H W
HW
Gong
Y
Y
Zulli
A
A
Perrone
M H
MH
Dunwiddie
C T
CT
Leadley
R J
RJ
D000818:Animals; D001780:Blood Coagulation Tests; D002339:Carotid Arteries; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000037:antagonists & inhibitors; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D007601:Jugular Veins; D007700:Kinetics; D008567:Membranes, Artificial; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy*
D003497:Cyclic N-Oxides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D008567:Membranes, Artificial; D011725:Pyridines; D015842:Serine Proteinase Inhibitors; C022475:prothrombinase complex; D005165:Factor V; D015951:Factor Xa; C435830:otamixaban