SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human
coagulation factor Xa (fXa) (K(i) = 0.52 nM). This study compared the antithrombotic effects of SK549 and a series of
benzamidine isoxazoline fXa inhibitors with
aspirin,
DuP 714 (a
direct thrombin inhibitor), recombinant
tick anticoagulant peptide, or
heparin in a rabbit model of electrically induced carotid arterial
thrombosis. Compounds were infused i.v. continuously from 60 min before electrical stimulation to the end of the experiment. Values of ED(50) (dose that increases the carotid blood flow to 50% of the control) were 0.12 micromol/kg/h for SK549, 0.56 micromol/kg/h for
aspirin, 0.14 micromol/kg/h for
DuP 714, 0.06 micromol/kg/h for recombinant
tick anticoagulant peptide, and >100 U/kg/h for
heparin. The EC(50) (plasma concentration that increased blood flow to 50% of the control) for SK549 was 97 nM. Unlike
aspirin and
heparin, SK549 was efficacious and, at 1.5 micromol/kg/h i.v. (n = 9), maintained carotid blood flow at 87 +/- 6% of control level for greater than 90 min. Unlike
heparin, SK549 inhibited ex vivo fXa activity but not ex vivo
thrombin activity. There was a highly significant correlation between K(i) (fXa) and ED(50) of a series of fXa inhibitors (r = 0. 85, P <.001). Therefore, these results suggest that SK549 is a novel, potent, and effective
antithrombotic agent in a rabbit model of arterial
thrombosis. It is likely that SK549 exerts its antithrombotic effect through selective inhibition of fXa. Furthermore, SK549 may be clinically useful for the prevention of arterial
thrombosis.