Abstract
A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as KIand IC50, respectively. A highly significant correlation was found between KI and IC50(r = 0.93, P < .0001). The antithrombotic effects of SF303 [mol. wt. 536;KI: fXa, 6.3 nM; thrombin, 3,100 nM; trypsin, 110 nM; tissue plasminogen activator >20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; KI: fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [KI(fXa) = 0.5 nM], DX-9065a [KI(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID50 values for preventing arteriovenous shunt-induced thrombosis were 0.6 μmol/kg/h for SF303, 0.035 μmol/kg/h for SK549, 0.01 μmol/kg/h for recombinant tick anticoagulant peptide, 0.4 μmol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC50 of 0.062 μM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 ± 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents.
Footnotes
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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
- Abbreviations:
- LMWH
- low molecular weight heparin
- fXa
- factor Xa
- APTT
- activated partial thromboplastin time
- AV
- arteriovenous
- AVST
- arteriovenous shunt thrombosis
- GP
- glycoprotein
- PT
- prothrombin time
- rTAP
- recombinant tick anticoagulant peptide
- tPA
- tissue plasminogen activator
- Received June 22, 1999.
- Accepted September 23, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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