Abstract
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.
Footnotes
-
Send reprint requests to: Dr. Pancras C. Wong, DuPont Pharmaceuticals Company, P.O. Box 80400, Wilmington, DE 19880-0400. E-mail: pancras.c.wong{at}dupontpharma.com
-
↵1 Presented in part at the 72nd Scientific Sessions of the American Heart Association, November 7–10, 1999, Atlanta, Georgia (Abstr. 2483).
-
↵2 Current address: Tularik, Inc., South San Francisco, CA.
- Abbreviations:
- fXa
- factor Xa
- SK549
- (−)-5-isoxazolecarboxamide, 3-[3-(aminoiminomethyl)phenyl]-N-5-[2′-(aminosulfonyl)-[1,1′-biphenyl]-4-yl]-4,5-dihydro-5-(1H-tetrazol-1-ylmethyl)-trifluoroacetic acid salt
- ECAT
- electrical current-induced arterial thrombosis
- rTAP
- recombinant tick anticoagulant peptide
- APTT
- activated partial thromboplastin time
- PT
- prothrombin time
- TT
- thrombin time
- Received April 12, 2000.
- Accepted June 30, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|