DPC423 [1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-
biphenyl]-4-yl]-3-(trifluoromethyl)-1H-
pyrazole-5-carboxamide] is a synthetic, competitive, and selective inhibitor of
coagulation factor Xa (fXa) (K(i): 0.15 nM in humans, 0.3 nM in rabbit). The objective of this study was to compare effects of
DPC423,
enoxaparin (
low-molecular-weight heparin), and
argatroban (
thrombin inhibitor) on arterial
thrombosis and hemostasis in rabbit models of electrically induced
carotid artery thrombosis and cuticle
bleeding, respectively. Compounds were infused i.v. continuously from 60 min before artery injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. Antithrombotic ED(50) values were 0.4 mg/kg/h for
enoxaparin (n = 6), 0.13 mg/kg/h for
argatroban (n = 6), and 0.6 mg/kg/h for
DPC423 (n = 12).
DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n = 6) by 1.8 +/- 0.07- and 1.8 +/- 0.13-fold, respectively, without changes in thrombin time and ex vivo
thrombin activity. The antithrombotic effect of
DPC423 was significantly correlated with its ex vivo anti-fXa activity (r = 0.86).
DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 +/- 4, 24 +/- 6, and 74 +/- 7, respectively (n = 6/group). Cuticle bleeding times (percent change over control) determined at the maximum antithrombotic dose were 88 +/- 12 for
argatroban, 69 +/- 13 for
heparin, 4 +/- 3 for
enoxaparin, 5 +/- 4 for
DPC423, and -3 +/- 2 for the vehicle (n = 5-6/group), suggesting dissociation of antithrombotic and bleeding time effects for
DPC423 and
enoxaparin. The combination of
aspirin and
DPC423 at ineffective antithrombotic doses produced significant antithrombotic effect. Therefore, these results suggest that
DPC423 is a clinically useful oral
anticoagulant for the prevention of arterial
thrombosis.