RT Journal Article
SR Electronic
T1 Nonpeptide Factor Xa Inhibitors II. Antithrombotic Evaluation in a Rabbit Model of Electrically Induced Carotid Artery Thrombosis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 212
OP 218
VO 295
IS 1
A1 Pancras C. Wong
A1 Earl J. Crain
A1 Robert M. Knabb
A1 Raymond P. Meade
A1 Mimi L. Quan
A1 Carol A. Watson
A1 Ruth R. Wexler
A1 Matthew R. Wright
A1 Andrew M. Slee
YR 2000
UL http://jpet.aspetjournals.org/content/295/1/212.abstract
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