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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 30, 2004; DOI: 10.1124/jpet.104.079301

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Received for publication October 18, 2004.
Revised November 16, 2004.
Accepted for publication November 18, 2004.

In vitro and in vivo pharmacological characterization of BM-613, a novel dual thromboxane synthase inhibitor and thromboxane receptor antagonist

Julien Hanson 1*, Stephanie Rolin 2, Denis Reynaud 3, Na Qiao 3, Leanne P. Kelley 4, Helen M. Reid 4, Francois Valentin 5, John Tippins 5, B. Therese Kinsella 4, Bernard Masereel 2, Cecil Pace-Asciak 3, Bernard Pirotte 1, Jean-Michel P.N. Dogne 1

1 University of Liege 2 FUNDP 3 The Hospital for Sick Children 4 University College Dublin 5 Imperial College

* Address correspondence to: E-mail: j.hanson{at}ulg.ac.be

Abstract

Thromboxane (TXA2) is a key mediator of platelet aggregation and smooth muscle contraction. Its action is mediated by its G-protein coupled receptor of which two isoforms, termed TP{alpha} and TP{beta}, occur in humans. TXA2 has been implicated in pathologies such as cardiovascular diseases, pulmonary embolism, atherosclerosis and asthma. This study describes the pharmacological characterization of BM-613, a new combined TXA2 receptor antagonist and TXA2 synthase inhibitor. It exhibits a strong affinity for human platelet TP receptors (IC50: 1.4 nM), TP{alpha} and TP{beta} expressed in COS-7 cells (IC50: 2.06 nM and 3.1 nM, respectively) and TPs expressed in human coronary artery smooth muscle cells (IC50: 29 µM). BM-613 shows a weak ability to prevent contraction of isolated rat aorta (ED50: 1.52 µM) and guinea-pig trachea (ED50: 2.5 µM) induced by TXA2 agonist U-46619. Besides, BM-613 antagonizes TP{alpha} (IC50: 0.11 µM) and TP{beta} (IC50: 0.17 µM) calcium mobilization induced by U-46619 and inhibits human platelet aggregation induced by U-46619 (ED50: 0.278 µM), arachidonic acid (ED50: 0.375 µM) and the second wave of ADP. BM-613 also dose-dependently prevents TXA2 production by human platelets (IC50: 0.15 µM). In a rat model of ferric chloride induced thrombosis, BM-613 significantly reduces weight of formed thrombus by 79%, 49% and 28% at 5, 2 and 1 mg/kg (i.v.), respectively. In conclusion, BM-613 is a dual and potent TP receptor antagonist and TXA2 synthase inhibitor characterized by a strong antiplatelet and antithrombotic potency. These results suggest that BM-613 could be a potential therapeutic drug for thrombotic disorders.


Key words: TP receptor, Thromboxane A2, antiplatelet agent, antithrombotic drug, eicosanoid, platelet aggregation


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