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Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics.

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.
AuthorsP C Wong, M L Quan, E J Crain, C A Watson, R R Wexler, R M Knabb
JournalThe 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
PMID10604970 (Publication Type: Comparative Study, Journal Article)
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
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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