Synthesis and pharmacological evaluation of a new targeted drug carrier system: β-Cyclodextrin coupled to oxytocin

in Bioorganic & Medicinal Chemistry Letters (2008), 18

β-Cyclodextrin (β-CD) was monofunctionalized into its carboxylic derivative and then conjugated to the N-side of oxytocin (OT), a nonapeptide involved in human behavior and myometrium contraction. On ... [more ▼]

β-Cyclodextrin (β-CD) was monofunctionalized into its carboxylic derivative and then conjugated to the N-side of oxytocin (OT), a nonapeptide involved in human behavior and myometrium contraction. On isolated rat myometrium, this conjugate (β-CD-OT) partly preserves the contracting activity of OT (EC50 = 0.40 μM vs 1.7 nM). Moreover, the contraction induced frequency is also lowered by β-CD-OT. This novel hydrophilic targeted carrier could form a host–guest complex with prostaglandins and their derivatives used as labor inducers or with anticancer drugs used in cervix and endometrial cancer. This strategy can improve the solubility, the stability, and/or the biological activity of these drugs as well as reducing their side-effects. [less ▲]

Comparative effects on LV performance, arterial hemodynamics and ventriculo-arterial coupling of two porcine models of coronary artery occlusion

Conference (2007, April 21)

Hemodynamic evaluation of two models of coronary artery occlusion in pigs

in Acta Cardiologica (2007)

Evaluation of BM-573, a novel TXA(2) synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion

in Prostaglandins & Other Lipid Mediators (2006), 79(1-2), 53-73

Aims: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylam\ino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A(2) synthase inhibitor and receptor antagonist, prevents ... [more ▼]

Aims: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylam\ino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A(2) synthase inhibitor and receptor antagonist, prevents reperfusion injury in acutely ischemic pigs. Methods: Twelve animals were randomly divided in two groups: a control group (n = 6) intravenously infused with vehicle, and a BM-573-treated group (n = 6) infused with BM-573 (10 mg kg(-1) h(-1)). In both groups, the left anterior descending (LAD) coronary artery was Occluded for 60 min and reperfused for 240 min. Either vehicle or BM-573 was infused 30 min before LAD occlusion and throughout the experiment. Platelet aggregation induced by arachidonic acid ex vivo measured was prevented by BM-573. Results: In both groups, LAD occlusion decreased cardiac output, ejection fraction, slope of stroke work-end-diastolic volume relationship, and induced end-systolic pressure-volume relationship (ESPVR) rightward shift, while left ventricular afterload increased. Ventriculo-arterial coupling and mechanical efficiency decreased. In both groups, reperfusion further decreased cardiac output and ejection fraction, while ESPVR displayed a further rightward shift. Ventriculo-arterial coupling and mechanical efficiency remained impaired. Area at risk, evidenced with Evans blue, was 33.2 +/- 3.4% of the LV mass (LVM) in both groups, and mean infarct size, revealed by triphenyltetrazolium chloride (TTC), was 27.3 +/- 2.6% of the LVM in the BM-573-treated group (NS). Histological examination and immunohistochemical identification of desmin revealed necrosis in the anteroseptal region similar in both groups, while myocardial ATP dosages and electron microscopy also showed that BM-573 had no cardioprotective effect. Conclusions: These data suggest that BM-573 failed to prevent reperfusion injury in acutely ischemic pigs. (C) 2005 Elsevier Inc. All rights reserved. [less ▲]

Synthèse et évaluation pharmacologique de nouveaux antagonistes du récepteur au thromboxane A2 dérivés du BM-573

Poster (2004, June)

Characterization of preferential activity on platelet thromboxane A2 receptors of BM-613, a new thromboxane A2 antagonist

in Fundamental & Clinical Pharmacology (2004)

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

in Journal of Pharmacology and Experimental Therapeutics (The) (2004), 309(2), 498-505

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 ... [more ▼]

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 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+/-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. [less ▲]

Antithrombotic activity of BM-573, a novel thromboxane modulator, in rat arterial thrombosis model, pig myocardial infarction model and its effect on bleeding time

Poster (2003, December)

BM-613, a new thromboxane A2 antagonist, is characterized by a preferential activity on platelet thromboxane A2 receptors

Poster (2003, November 22)

BM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, prevents pig myocardial infarction induced by coronary thrombosis

in Journal of Pharmacology and Experimental therapeutics (2003), 306(1), 59-65

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 A 2 receptor antagonist and thromboxane ... [more ▼]

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 A 2 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. [less ▲]