Nonpeptide factor Xa inhibitors II. Antithrombotic evaluation in a rabbit model of electrically induced carotid artery thrombosis

SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human coagul ation factor Xa (fXa) (K-i = 0.52 nM). This study compared the antithrombot ic effects of SK549 and a series of benzamidine isoxazoline fXa inhibitors with aspirin, DuP 714 (a direct thrombin inhibitor), recombinant tick antic oagulant peptide, or heparin in a rabbit model of electrically induced caro tid arterial thrombosis. Compounds were infused i.v. continuously from 60 m in 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 mu mol/kg/h for SK549, 0.56 mu mol/kg/h for aspirin, 0.14 mu mol/kg/h for DuP 714, 0.06 mu mol/kg/h for recombinant tick anticoagulant peptide, a nd >100 U/kg/h for heparin. The EC50 (plasma concentration that increased b lood flow to 50% of the control) for SK549 was 97 nM. Unlike aspirin and he parin, SK549 was efficacious and, at 1.5 mu mol/kg/h i.v. (n = 9), maintain ed 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 thro mbin activity. There was a highly significant correlation between K-i (fXa) and ED50 of a series of fXa inhibitors (r = 0.85, P < .001). Therefore, th ese results suggest that SK549 is a novel, potent, and effective antithromb otic agent in a rabbit model of arterial thrombosis. It is likely that SK54 9 exerts its antithrombotic effect through selective inhibition of fXa. Fur thermore, SK549 may be clinically useful for the prevention of arterial thr ombosis.