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Research ArticleCARDIOVASCULAR

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

Jean-Michel Dogné, Julien Hanson, Xavier de Leval, Philippe Kolh, Vincent Tchana-Sato, Laurence de Leval, Stéphanie Rolin, Alexandre Ghuysen, Patrick Segers, Bernard Lambermont, Bernard Masereel and Bernard Pirotte
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 498-505; DOI: https://doi.org/10.1124/jpet.103.063610
Jean-Michel Dogné
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Julien Hanson
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Xavier de Leval
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Philippe Kolh
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Vincent Tchana-Sato
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Laurence de Leval
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Stéphanie Rolin
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Alexandre Ghuysen
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Patrick Segers
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Bernard Lambermont
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Bernard Masereel
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Bernard Pirotte
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Abstract

The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2)-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 ± 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 ± 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia.

Footnotes

  • This work was supported by Fonds de la Recherche Scientifique Médicale Grant 3.4.505.01.F. Vincent Tchana-Sato is a Research Fellow of the Fonds National de la Recherche Scientifique (FNRS), and Laurence de Leval is a Research Associate of the FNRS.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.063610.

  • ABBREVIATIONS: COX, cyclooxygenase; TXA2, thromboxane A2; ASA, aspirin; PG, prostaglandin; PGH2, prostaglandin endoperoxide H2; TP, TXA2 receptor; PGI2, prostacyclin; BM-573, N-tert-butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea; U-46619, 9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2; BT, bleeding time; HPLC, high-performance liquid chromatography; TTO, time to occlusion; TXRA, thromboxane receptor antagonist; TXSI, thromboxane synthase inhibitor; Z-335, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate; BMS-180291, [(+)1S-(1α,2α,3α,4α)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid].

    • Received November 28, 2003.
    • Accepted January 16, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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Research ArticleCARDIOVASCULAR

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

Jean-Michel Dogné, Julien Hanson, Xavier de Leval, Philippe Kolh, Vincent Tchana-Sato, Laurence de Leval, Stéphanie Rolin, Alexandre Ghuysen, Patrick Segers, Bernard Lambermont, Bernard Masereel and Bernard Pirotte
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 498-505; DOI: https://doi.org/10.1124/jpet.103.063610

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Research ArticleCARDIOVASCULAR

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

Jean-Michel Dogné, Julien Hanson, Xavier de Leval, Philippe Kolh, Vincent Tchana-Sato, Laurence de Leval, Stéphanie Rolin, Alexandre Ghuysen, Patrick Segers, Bernard Lambermont, Bernard Masereel and Bernard Pirotte
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 498-505; DOI: https://doi.org/10.1124/jpet.103.063610
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