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CARDIOVASCULAR

In Vitro and in Vivo Pharmacological Characterization of BM-613 [N-n-Pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a Novel Dual Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist

Natural and Synthetic Drugs Research Centre, Department of Pharmacy, Laboratory of Medicinal Chemistry, University of Liège, Liège, Belgium (J.H., J.-M.D., B.P.); Department of Pharmacy, University of Namur, Namur, Belgium (S.R., B.M.); Programme in Integrative Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (D.R., N.Q., C.P.-A.); Department of Biochemistry, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Ireland (L.P.K., H.M.R., B.T.K.); and Department of Biological Sciences, Imperial College, London, United Kingdom (F.V., J.T.)

Thromboxane A₂ (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 and TP, 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 [N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], 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 and TP expressed in COS-7 cells (IC₅₀ = 2.1 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 (9.11-dideoxy-9.11-methanoepoxy-prostaglandin F₂). Besides, BM-613 antagonizes TP (IC₅₀ = 0.11 µM) and TP (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.

Address correspondence to: Julien Hanson, Natural and Synthetic Drugs Research Centre, Department of Pharmacy, Laboratory of Medicinal Chemistry, University of Liège, 1, Av de L'hôpital, 4000 Liège, Belgium. E-mail: j.hanson{at}ulg.ac.be

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