DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles.
BACKGROUND
Factor Xa (FXa), a key serine protease that converts prothrombin to thrombin in the coagulation cascade, is a promising target enzyme for the prophylaxis and treatment of thromboembolic diseases. DU-176b is a novel antithrombotic agent that directly inhibits FXa activity.


OBJECTIVE
To evaluate the in vitro pharmacological profiles and in vivo effects of DU-176b in animal models of thrombosis and bleeding.


METHODS
In vitro, FXa inhibition, specificity and anticoagulant activities were examined. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail bleeding.


RESULTS
DU-176b inhibited FXa with Ki values of 0.561 nm for free FXa, 2.98 nm for prothrombinase, and exhibited >10 000-fold selectivity for FXa. In human plasma, DU-176b doubled prothrombin time and activated partial thromboplastin time at concentrations of 0.256 and 0.508 microm, respectively. DU-176b did not impair platelet aggregation by ADP, collagen or U46619. DU-176b was highly absorbed in rats and monkeys, as demonstrated by more potent anti-Xa activity and higher drug concentration in plasma following oral administration than a prototype FXa inhibitor, DX-9065a. In vivo, DU-176b dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, although bleeding time in rats was not significantly prolonged at an antithrombotic dose.


CONCLUSIONS
DU-176b is a more potent and selective FXa inhibitor with high oral bioavailability compared with its prototype, DX-9065a. DU-176b represents a promising new anticoagulant for the prophylaxis and treatment of thromboembolic diseases.
Furugohri
T
T
Biological Research Laboratories I, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Toyo, Japan.
Isobe
K
K
Honda
Y
Y
Kamisato-Matsumoto
C
C
Sugiyama
N
N
Nagahara
T
T
Morishima
Y
Y
Shibano
T
T
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D065427:Factor Xa Inhibitors; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D065427:Factor Xa Inhibitors; D011725:Pyridines; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; C552171:edoxaban