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 K(I) and IC(50), respectively. A highly significant correlation was found between K(I) and IC(50) (r = 0.93, P <.0001). The antithrombotic effects of SF303 [mol. wt. 536; K(I): 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; K(I): 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 [K(I)(fXa) = 0.5 nM], DX-9065a [K(I)(fXa) = 30 nM], and heparin or low molecular weight heparin ( dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID(50) values for preventing arteriovenous shunt-induced thrombosis were 0.6 micromol/kg/h for SF303, 0.035 micromol/kg/h for SK549, 0.01 micromol/kg/h for recombinant tick anticoagulant peptide, 0.4 micromol/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 IC(50) of 0.062 microM. 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.
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Authors | P C Wong, M L Quan, E J Crain, C A Watson, R R Wexler, R M Knabb |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 292
Issue 1
Pg. 351-7
(Jan 2000)
ISSN: 0022-3565 [Print] United States |
PMID | 10604970
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- (2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid
- Anticoagulants
- Factor Xa Inhibitors
- Fibrinolytic Agents
- Isoxazoles
- Naphthalenes
- Propionates
- Recombinant Proteins
- SF 303
- SK 549
- Sulfonamides
- Tetrazoles
- Heparin
- Dalteparin
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Topics |
- Animals
- Anticoagulants
(pharmacology)
- Arteriovenous Shunt, Surgical
- Blood Coagulation
(drug effects)
- Dalteparin
(pharmacology)
- Dose-Response Relationship, Drug
- Factor Xa Inhibitors
- Fibrinolytic Agents
(pharmacology, therapeutic use)
- Heparin
(pharmacology)
- Humans
- In Vitro Techniques
- Isoxazoles
(pharmacology, therapeutic use)
- Male
- Naphthalenes
(pharmacology)
- Platelet Aggregation
(drug effects)
- Propionates
(pharmacology)
- Rabbits
- Recombinant Proteins
(pharmacology)
- Sulfonamides
(pharmacology)
- Tetrazoles
(pharmacology, therapeutic use)
- Thrombosis
(drug therapy)
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