The Experts below are selected from a list of 1308 Experts worldwide ranked by ideXlab platform
Bernard Masereel - One of the best experts on this subject based on the ideXlab platform.
-
JPET #63610 1
2016Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Bernard Masereel, Stephanie Rolin, Xavier De Leval, Patrick Segers, Vincent Tchana-sato, Re Ghuysen, Bernard PirotteAbstract:Pharmacological characterization of BM-573, a novel Thromboxane A2 receptor antagonist and Thromboxane Synthase Inhibitor in a rat model of arterial thrombosis and its effects on bleeding tim
-
bm 573 inhibits the development of early atherosclerotic lesions in apo e deficient mice by blocking tp receptors and Thromboxane Synthase
Prostaglandins & Other Lipid Mediators, 2011Co-Authors: Celine Cherdon, Carine Michiels, Julien Hanson, Annie Ooms, Pierre Drion, Bernard Pirotte, Laurence De Leval, S. Rolin, Bernard Masereel, Natzi SakalihassanAbstract:Abstract Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which Thromboxane A 2 (TXA 2 ) and 8-iso-PGF 2α have recently received a lot of attention. This study aimed to investigate the effect of a dual Thromboxane Synthase Inhibitor and Thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB 2 synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF 2α . Our results show that a molecule combining receptor antagonism and Thromboxane Synthase inhibition is more efficient in delaying atherosclerosis in Apo E −/− mice than sole inhibition of TXA 2 formation.
-
design synthesis and biological evaluation of a sulfonylcyanoguanidine as Thromboxane a2 receptor antagonist and Thromboxane Synthase Inhibitor
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Jean-michel Dogné, Catherine Michaux, François Durant, Jacques Delarge, Stephanie Rolin, Johan Wouters, Lionel Pochet, Bernard MasereelAbstract:The synthesis and the structure of N-isopropyl-N'-[2-(3'-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two Thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the Thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 microM) with an IC50 value of 0.45 and 0.15 microM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 microM) completely inhibited TXA2 Synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
-
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.
-
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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Julien Hanson, Stephanie Rolin, Denis Reynaud, Na Qiao, Leanne P Kelley, Helen M Reid, Francois Valentin, John R Tippins, Therese B Kinsella, Bernard MasereelAbstract: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 TPα and TPβ, 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), TPα and TPβ 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 TPα (IC50 = 0.11 μM) and TPβ (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.
Jean-michel Dogné - One of the best experts on this subject based on the ideXlab platform.
-
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
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
-
JPET #63610 1
2016Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Bernard Masereel, Stephanie Rolin, Xavier De Leval, Patrick Segers, Vincent Tchana-sato, Re Ghuysen, Bernard PirotteAbstract:Pharmacological characterization of BM-573, a novel Thromboxane A2 receptor antagonist and Thromboxane Synthase Inhibitor in a rat model of arterial thrombosis and its effects on bleeding tim
-
effects of the dual tp receptor antagonist and Thromboxane Synthase Inhibitor ev 077 on human endothelial and vascular smooth muscle cells
Biochemical and Biophysical Research Communications, 2013Co-Authors: Marcelo H. Petri, Celine Tellier, Carine Michiels, Ingvill Ellertsen, Jean-michel Dogné, Magnus BackAbstract:Abstract The prothrombotic mediator Thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and Thromboxane Synthase pathways, and transduces its effect through the Thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and Thromboxane Synthase Inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this Thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a Thromboxane mimetic, supporting that the Thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.
-
design synthesis and biological evaluation of a sulfonylcyanoguanidine as Thromboxane a2 receptor antagonist and Thromboxane Synthase Inhibitor
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Jean-michel Dogné, Catherine Michaux, François Durant, Jacques Delarge, Stephanie Rolin, Johan Wouters, Lionel Pochet, Bernard MasereelAbstract:The synthesis and the structure of N-isopropyl-N'-[2-(3'-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two Thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the Thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 microM) with an IC50 value of 0.45 and 0.15 microM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 microM) completely inhibited TXA2 Synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
-
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.
Stephanie Rolin - One of the best experts on this subject based on the ideXlab platform.
-
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
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
-
JPET #63610 1
2016Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Bernard Masereel, Stephanie Rolin, Xavier De Leval, Patrick Segers, Vincent Tchana-sato, Re Ghuysen, Bernard PirotteAbstract:Pharmacological characterization of BM-573, a novel Thromboxane A2 receptor antagonist and Thromboxane Synthase Inhibitor in a rat model of arterial thrombosis and its effects on bleeding tim
-
design synthesis and biological evaluation of a sulfonylcyanoguanidine as Thromboxane a2 receptor antagonist and Thromboxane Synthase Inhibitor
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Jean-michel Dogné, Catherine Michaux, François Durant, Jacques Delarge, Stephanie Rolin, Johan Wouters, Lionel Pochet, Bernard MasereelAbstract:The synthesis and the structure of N-isopropyl-N'-[2-(3'-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two Thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the Thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 microM) with an IC50 value of 0.45 and 0.15 microM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 microM) completely inhibited TXA2 Synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
-
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.
-
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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Julien Hanson, Stephanie Rolin, Denis Reynaud, Na Qiao, Leanne P Kelley, Helen M Reid, Francois Valentin, John R Tippins, Therese B Kinsella, Bernard MasereelAbstract: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 TPα and TPβ, 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), TPα and TPβ 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 TPα (IC50 = 0.11 μM) and TPβ (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.
Julien Hanson - One of the best experts on this subject based on the ideXlab platform.
-
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
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
-
JPET #63610 1
2016Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Bernard Masereel, Stephanie Rolin, Xavier De Leval, Patrick Segers, Vincent Tchana-sato, Re Ghuysen, Bernard PirotteAbstract:Pharmacological characterization of BM-573, a novel Thromboxane A2 receptor antagonist and Thromboxane Synthase Inhibitor in a rat model of arterial thrombosis and its effects on bleeding tim
-
bm 573 inhibits the development of early atherosclerotic lesions in apo e deficient mice by blocking tp receptors and Thromboxane Synthase
Prostaglandins & Other Lipid Mediators, 2011Co-Authors: Celine Cherdon, Carine Michiels, Julien Hanson, Annie Ooms, Pierre Drion, Bernard Pirotte, Laurence De Leval, S. Rolin, Bernard Masereel, Natzi SakalihassanAbstract:Abstract Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which Thromboxane A 2 (TXA 2 ) and 8-iso-PGF 2α have recently received a lot of attention. This study aimed to investigate the effect of a dual Thromboxane Synthase Inhibitor and Thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB 2 synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF 2α . Our results show that a molecule combining receptor antagonism and Thromboxane Synthase inhibition is more efficient in delaying atherosclerosis in Apo E −/− mice than sole inhibition of TXA 2 formation.
-
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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Julien Hanson, Stephanie Rolin, Denis Reynaud, Na Qiao, Leanne P Kelley, Helen M Reid, Francois Valentin, John R Tippins, Therese B Kinsella, Bernard MasereelAbstract: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 TPα and TPβ, 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), TPα and TPβ 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 TPα (IC50 = 0.11 μM) and TPβ (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.
-
effect of bm 573 n terbutyl n 2 4 methylphenylamino 5 nitro benzenesulfonyl urea a dual Thromboxane Synthase Inhibitor and Thromboxane receptor antagonist in a porcine model of acute pulmonary embolism
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Alexandre Ghuysen, Julien Hanson, Jean-michel Dogné, Philippe Kolh, Vincent Tchanasato, Patrick Segers, Bernard Lambermont, Philippe Morimont, David Magis, Vincent DorioAbstract:The aim of this study was to evaluate the effect of BM-573 [ N -terbutyl- N ′-[2-(4′-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a dual Thromboxane A 2 Synthase Inhibitor and receptor antagonist, on the hemodynamic response to acute pulmonary embolism. Six anesthetized pigs were infused with placebo (placebo group) and compared with six other pigs receiving a continuous infusion of BM-573 (BM group). Pulmonary embolization with 0.3 g/kg autologous blood clots was carried out 30 min after the start of the infusion. Right ventricular pressure-volume loops were recorded using a conductance catheter, and end-systolic ventricular elastance was periodically assessed by varying right ventricular preload. Pulmonary vascular properties were studied by use of a four-element windkessel model. Hemodynamic data, including assessment of right ventricular-arterial coupling, were collected at baseline and every 30 min for 4 h. Blood samples were collected to assess gas exchange, Thromboxane A 2 , and prostacyclin plasma levels and to evaluate platelet aggregation. Mean pulmonary arterial pressure in the placebo group increased significantly more than in the BM group, mainly because of an additional increase in pulmonary vascular resistance. Arterial and end-systolic ventricular elastances increased also more in the placebo group, whereas right ventricular efficiency decreased. BM-573 prevented both platelet aggregation induced by U-46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F 2α ) or by arachidonic acid, and Thromboxane A 2 overproduction, whereas prostacyclin liberation was preserved. Oxygenation, however, was not significantly improved. We conclude that in this animal model of acute pulmonary embolism, infusion of BM-573 reduced pulmonary vasoconstriction. As a result, right ventricular-vascular coupling values were maintained at a maximal efficiency level.
John Steele - One of the best experts on this subject based on the ideXlab platform.
-
Thromboxane modulating agents. 3. 1H-imidazol-1-ylalkyl- and 3-pyridinylalkyl-substituted 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid derivatives as dual Thromboxane Synthase Inhibitor/Thromboxane receptor antagonists.
Journal of Medicinal Chemistry, 1997Co-Authors: Roger Peter Dickinson, Kevin Neil Dack, Clive J. Long, John SteeleAbstract:The design of a series of dual Thromboxane Synthase Inhibitor/Thromboxane receptor antagonists based on a 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid Thromboxane receptor antagonist template is described. Introduction of a 5-(1H-imidazol-1-ylmethyl), a 5-(3-pyridinylmethyl), or a 5-(3-pyridinyloxy) substituent leads to dual agents with Thromboxane Synthase Inhibitory activity comparable with that of dazmegrel (7). In addition, 3-pyridinylalkyl substituents also make a significant contribution to Thromboxane receptor binding. Oral administration of compound 74 (5 mg/kg) to conscious dogs produces long-lasting Thromboxane Synthase inhibition and Thromboxane receptor blockade as measured by inhibition of U46619-induced platelet aggregation ex vivo.
-
Thromboxane modulating agents. 2. Thromboxane receptor antagonists derived from the Thromboxane Synthase Inhibitor dazmegrel.
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Roger Peter Dickinson, Kevin Neil Dack, John Steele, Michael S. TuteAbstract:Abstract The design of dual Thromboxane Synthase Inhibitor/Thromboxane receptor antagonists (e.g. 15 ) based on the structure of the Thromboxane Synthase Inhibitor dazmegrel is described. More potent receptor antagonists (e.g. 16c ) result from replacement of the pyridinyl subsituent with 4-fluorophenyl. Modelling suggests the existence of more than one site capable of interacting with the aryl sulfonamide of TxA 2 receptor antagonists.
-
Thromboxane modulating agents 1 design of 1 arylsulfonyl amino alkylindole derivatives as dual Thromboxane Synthase Inhibitor Thromboxane receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Dickinson Roger Peter, Dack Kevin Neil, John SteeleAbstract:Abstract The design of a series of dual Thromboxane Synthase Inhibitor/Thromboxane receptor antagonists based on an indole Thromboxane Synthase Inhibitor template is described. The indole-5-propanoic acid derivatives 17, 22 and 23 were found to be potent dual agents in vitro.