title: 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.
abstract: 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 TPalpha and TPbeta, 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), TPalpha and TPbeta expressed in COS-7 cells (IC(50) = 2.1 and 3.1 nM, respectively), and TPs expressed in human coronary artery smooth muscle cells (IC50 = 29 microM). BM-613 shows a weak ability to prevent contraction of isolated rat aorta (ED50 = 1.52 microM) and guinea pig trachea (ED50 = 2.5 microM) induced by TXA2 agonist U-46619 (9.11-dideoxy-9.11-methanoepoxy-prostaglandin F2). Besides, BM-613 antagonizes TPalpha (IC50 = 0.11 microM) and TPbeta (IC50 = 0.17 microM) calcium mobilization induced by U-46619 and inhibits human platelet aggregation induced by U-46619 (ED50 = 0.278 microM), arachidonic acid (ED50 = 0.375 microM), and the second wave of ADP. BM-613 also dose dependently prevents TXA2 production by human platelets (IC50 = 0.15 microM). 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.
authors.affiliation: Natural and Synthetic Drugs Research Centre, Department of Pharmacy, Laboratory of Medicinal Chemistry, University of Liège, 1, Av de L'hôpital, 4000 Liège, Belgium. j.hanson@ulg.ac.be
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rolin
authors.forename: Denis
authors.initials: D
authors.lastname: Reynaud
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.forename: Leanne P
authors.initials: LP
authors.lastname: Kelley
authors.forename: Helen M
authors.initials: HM
authors.lastname: Reid
authors.forename: François
authors.initials: F
authors.lastname: Valentin
authors.forename: John
authors.initials: J
authors.lastname: Tippins
authors.forename: B Therese
authors.initials: BT
authors.lastname: Kinsella
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Cecil
authors.initials: C
authors.lastname: Pace-Asciak
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014132:Trachea / Q000187:drug effects; D014162:Transfection
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; C500527:N-n-pentyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D013930:Thromboxane-A Synthase; D002118:Calcium