PT - JOURNAL ARTICLE AU - Pancras C. Wong AU - Earl J. Crain AU - Robert M. Knabb AU - Raymond P. Meade AU - Mimi L. Quan AU - Carol A. Watson AU - Ruth R. Wexler AU - Matthew R. Wright AU - Andrew M. Slee TI - Nonpeptide Factor Xa Inhibitors II. Antithrombotic Evaluation in a Rabbit Model of Electrically Induced Carotid Artery Thrombosis DP - 2000 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 212--218 VI - 295 IP - 1 4099 - http://jpet.aspetjournals.org/content/295/1/212.short 4100 - http://jpet.aspetjournals.org/content/295/1/212.full SO - J Pharmacol Exp Ther2000 Oct 01; 295 AB - SK549 (mol. wt. 546 Da) is a synthetic, selective inhibitor of human coagulation factor Xa (fXa) (Ki = 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 ED50 (dose that increases the carotid blood flow to 50% of the control) were 0.12 μmol/kg/h for SK549, 0.56 μmol/kg/h for aspirin, 0.14 μmol/kg/h for DuP 714, 0.06 μmol/kg/h for recombinant tick anticoagulant peptide, and >100 U/kg/h for heparin. The EC50 (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 μmol/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 betweenKi (fXa) and ED50 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. The American Society for Pharmacology and Experimental Therapeutics