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Jean-michel Dogné - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Characterization of N-tert-Butyl-NЈ-[2-(4Ј- methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A 2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bl
2020Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Alexandre Ghuysen, Patrick Segers, Vincent Tchana-sato, Bernard LambermontAbstract:ABSTRACT The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-NЈ-[2-(4Ј-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 F 2 )-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 Ϯ 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 Ϯ 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. The isozymes cyclooxygenase (COX)-1 and -2 catalyze the conversion of arachidonic acid into Thromboxane A 2 (TXA 2 ) and prostaglandins (PGs). The eicosanoid TXA 2 is the major COX-1 product of arachidonic acid metabolism in platelets
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a novel Thromboxane Receptor antagonist and synthase inhibitor bm 573 reduces development and progression of atherosclerosis in ldl Receptor deficient mice
European Journal of Pharmacology, 2007Co-Authors: Tillmann Cyrus, Jean-michel Dogné, Tao Ding, Domenico PraticoAbstract:Abstract Atherosclerosis is a chronic inflammatory disease of the vasculature influenced by a variety of mediators. Among them, prostanoids, which include prostacyclin and Thromboxane (Tx) A2, have recently received a lot of attention. Previous studies demonstrated that antagonism or deletion of the Receptor for TxA2 retards early atherogenesis in apolipoprotein E-deficient mice, but no data are available in low-density lipoprotein (LDL) Receptor deficient mice. In our study, we tested the effect of a novel TxA2 Receptor (TP) antagonist and synthase inhibitor, BM-573, on atherosclerosis development and progression in LDL Receptor deficient mice. To this end, the effect of 12 weeks treatment with BM-573 on early or established aortic atherosclerotic lesions of these mice was assessed. In both treatments, while BM-573 did not affect body weight, systolic blood pressure, total plasma cholesterol or triglycerides levels, it partially reduced TxA2 but did not affect prostacyclin biosynthesis. Moreover, BM-573 significantly decreased early atherogenesis and prevented progression of established atherosclerotic lesions. These results show for the first time that this dual Tx inhibitor is effective in reducing atherogenesis in the LDL Receptor deficient mice. They also demonstrate the novel concept that this therapeutic approach halts the progression of the disease and influences the cellular composition of the atherosclerotic plaques.
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pharmacology of the Thromboxane Receptor antagonist and Thromboxane synthase inhibitor bm 531
Cardiovascular Drug Reviews, 2006Co-Authors: Jean-michel Dogné, Jacques Delarge, Stephanie Rolin, Xavier De Leval, Patricia Benoit, Philippe Neven, Philippe Kolh, J Damas, J L David, Bernard MasereelAbstract:: BM-531 (N-tert-butyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, is a novel noncarboxylic Thromboxane Receptor antagonist and Thromboxane synthase inhibitor. Indeed, its affinity for human washed platelet TXA2 Receptors labeled with [3H]SQ-29548 (IC50 = 0.0078 microM) is higher than sulotroban (IC50 = 0.93 microM) and SQ-29548 (IC50 = 0.021 microM). Moreover, BM-531 is characterized by a potent antiaggregatory property. Indeed, on one hand, in human citrated platelet-rich plasma BM-531 prevents platelet aggregation induced by arachidonic acid (600 microM) (ED100 = 0.125 microM), U-46619, a stable TXA2 agonist (1 microM) (ED50 = 0.482 microM) or collagen (1 microgram/mL) (percentage of inhibition: 42.9% at 10 microM) and inhibits the second wave of ADP (2 microM)-induced aggregation. On the other hand, when BM-531 is incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA-100) is significantly prolonged. In addition, at the concentrations of 10 and 1 microM, BM-531 totally prevents the production of TXB2 by human platelets activated by arachidonic acid. Finally, at 10 microM, BM-531 significantly prevents rat fundus contractions induced by U-46619 but not by prostacyclin. These results suggest that BM-531, which is devoid of the diuretic property of torasemide, can be regarded as a promising antiplatelet agent.
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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
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Patrick Segers, Bernard LambermontAbstract: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.
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bm 573 a dual Thromboxane synthase inhibitor and Thromboxane Receptor antagonist prevents pig myocardial infarction induced by coronary thrombosis
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Stephanie Rolin, Jean-michel Dogné, Patricia Benoit, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Bernard Lambermont, M Petein, Bernard MasereelAbstract:The aim of this study was to characterize the effects of BM-573 [ N -terbutyl- N ′-[2-(4′-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual Thromboxane A2 Receptor antagonist and Thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals ( n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 ± 2.2 and 36.9 ± 2.1% of the left ventricular mass, respectively. In the BM-573-treated group ( n = 6), a drug infusion (10 mg · kg–1 · h–1) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction.
Bernard Lambermont - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Characterization of N-tert-Butyl-NЈ-[2-(4Ј- methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A 2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bl
2020Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Alexandre Ghuysen, Patrick Segers, Vincent Tchana-sato, Bernard LambermontAbstract:ABSTRACT The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-NЈ-[2-(4Ј-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 F 2 )-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 Ϯ 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 Ϯ 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. The isozymes cyclooxygenase (COX)-1 and -2 catalyze the conversion of arachidonic acid into Thromboxane A 2 (TXA 2 ) and prostaglandins (PGs). The eicosanoid TXA 2 is the major COX-1 product of arachidonic acid metabolism in platelets
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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
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Patrick Segers, Bernard LambermontAbstract: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.
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bm 573 a dual Thromboxane synthase inhibitor and Thromboxane Receptor antagonist prevents pig myocardial infarction induced by coronary thrombosis
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Stephanie Rolin, Jean-michel Dogné, Patricia Benoit, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Bernard Lambermont, M Petein, Bernard MasereelAbstract:The aim of this study was to characterize the effects of BM-573 [ N -terbutyl- N ′-[2-(4′-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual Thromboxane A2 Receptor antagonist and Thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals ( n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 ± 2.2 and 36.9 ± 2.1% of the left ventricular mass, respectively. In the BM-573-treated group ( n = 6), a drug infusion (10 mg · kg–1 · h–1) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction.
Ruth Jackson - One of the best experts on this subject based on the ideXlab platform.
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dual acting Thromboxane Receptor antagonist synthase inhibitors synthesis and biological properties of 2 substituted 4 3 pyridyl 1 3 dioxan 5 yl alkenoic acids
Journal of Medicinal Chemistry, 1995Co-Authors: Alan Wellington Faull, Andrew George Brewster, George R Brown, Michael James Smithers, Ruth JacksonAbstract:: The design, synthesis, and pharmacology of a new class of compounds possessing both Thromboxane Receptor antagonist and Thromboxane synthase inhibitory properties are described. Replacement of the phenol group of the known Thromboxane antagonist series 4(Z)-6-[(4RS,5SR)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl] hex-4-enoic acid by a 3-pyridyl group led to a series of compounds, 5, which were potent Thromboxane synthase inhibitors and weak Thromboxane antagonists. Further modifications at the dioxane C2 position led to compounds, 7, which were potent dual-acting agents. In the case of compound 7w, the dual activity was shown to reside almost exclusively in the (-)-enantiomer, 7x. Following oral dosing to rats and dogs, 7x (3 mg/kg) displayed significant dual activity over a period of at least 8 h.
Peter Herman - One of the best experts on this subject based on the ideXlab platform.
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hypersensitivity to Thromboxane Receptor mediated cerebral vasomotion and cbf oscillations during acute no deficiency in rats
PLOS ONE, 2010Co-Authors: Bela Horvath, Gabor Lenzser, Balazs Benyo, Tamas Nemeth, Rita Benkő, Andras Iring, Peter HermanAbstract:Background Low frequency (4–12 cpm) spontaneous fluctuations of the cerebrovascular tone (vasomotion) and oscillations of the cerebral blood flow (CBF) have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO) suppresses constitutively the release and vascular effects of Thromboxane A2 (TXA2), NO-deficiency is often associated with activation of Thromboxane Receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-Receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations.
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Hypersensitivity to Thromboxane Receptor mediated cerebral vasomotion and CBF oscillations during acute NO-deficiency in rats.
Public Library of Science (PLoS), 2026Co-Authors: Bela Horvath, Gabor Lenzser, Balazs Benyo, Tamas Nemeth, Andras Iring, Peter Herman, Rita Benko, Katalin Komjáti, Zsombor Lacza, Péter SándorAbstract:BACKGROUND: Low frequency (4-12 cpm) spontaneous fluctuations of the cerebrovascular tone (vasomotion) and oscillations of the cerebral blood flow (CBF) have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO) suppresses constitutively the release and vascular effects of Thromboxane A(2) (TXA(2)), NO-deficiency is often associated with activation of Thromboxane Receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-Receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations. METHODOLOGY/PRINCIPAL FINDINGS: Effects of pharmacological modulation of TP-Receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats) and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs) both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-Receptor agonist U-46619 (1 µg/kg i.v.) to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.v.) resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA(2) synthesis by ozagrel (10 mg/kg i.v.) attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632. CONCLUSION/SIGNIFICANCE: These results suggest that hypersensitivity of the TP-Receptor-Rho-kinase signaling pathway contributes to the development of low frequency cerebral vasomotion which may propagate to vasospasm in pathophysiological states associated with NO-deficiency
Stephanie Rolin - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Characterization of N-tert-Butyl-NЈ-[2-(4Ј- methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A 2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bl
2020Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Alexandre Ghuysen, Patrick Segers, Vincent Tchana-sato, Bernard LambermontAbstract:ABSTRACT The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-NЈ-[2-(4Ј-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 F 2 )-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 Ϯ 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 Ϯ 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. The isozymes cyclooxygenase (COX)-1 and -2 catalyze the conversion of arachidonic acid into Thromboxane A 2 (TXA 2 ) and prostaglandins (PGs). The eicosanoid TXA 2 is the major COX-1 product of arachidonic acid metabolism in platelets
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pharmacology of the Thromboxane Receptor antagonist and Thromboxane synthase inhibitor bm 531
Cardiovascular Drug Reviews, 2006Co-Authors: Jean-michel Dogné, Jacques Delarge, Stephanie Rolin, Xavier De Leval, Patricia Benoit, Philippe Neven, Philippe Kolh, J Damas, J L David, Bernard MasereelAbstract:: BM-531 (N-tert-butyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, is a novel noncarboxylic Thromboxane Receptor antagonist and Thromboxane synthase inhibitor. Indeed, its affinity for human washed platelet TXA2 Receptors labeled with [3H]SQ-29548 (IC50 = 0.0078 microM) is higher than sulotroban (IC50 = 0.93 microM) and SQ-29548 (IC50 = 0.021 microM). Moreover, BM-531 is characterized by a potent antiaggregatory property. Indeed, on one hand, in human citrated platelet-rich plasma BM-531 prevents platelet aggregation induced by arachidonic acid (600 microM) (ED100 = 0.125 microM), U-46619, a stable TXA2 agonist (1 microM) (ED50 = 0.482 microM) or collagen (1 microgram/mL) (percentage of inhibition: 42.9% at 10 microM) and inhibits the second wave of ADP (2 microM)-induced aggregation. On the other hand, when BM-531 is incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA-100) is significantly prolonged. In addition, at the concentrations of 10 and 1 microM, BM-531 totally prevents the production of TXB2 by human platelets activated by arachidonic acid. Finally, at 10 microM, BM-531 significantly prevents rat fundus contractions induced by U-46619 but not by prostacyclin. These results suggest that BM-531, which is devoid of the diuretic property of torasemide, can be regarded as a promising antiplatelet agent.
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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
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Patrick Segers, Bernard LambermontAbstract: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.
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bm 573 a dual Thromboxane synthase inhibitor and Thromboxane Receptor antagonist prevents pig myocardial infarction induced by coronary thrombosis
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Stephanie Rolin, Jean-michel Dogné, Patricia Benoit, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Bernard Lambermont, M Petein, Bernard MasereelAbstract:The aim of this study was to characterize the effects of BM-573 [ N -terbutyl- N ′-[2-(4′-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual Thromboxane A2 Receptor antagonist and Thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals ( n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 ± 2.2 and 36.9 ± 2.1% of the left ventricular mass, respectively. In the BM-573-treated group ( n = 6), a drug infusion (10 mg · kg–1 · h–1) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction.