Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents

in Journal of Pharmacology and Experimental Therapeutics (The) (2006), 318(3), 1057-1067

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A ... [more ▼]

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor ( VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 mu M. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca2+ pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11- dideoxy- 9,11- methanoepoxyprostaglandin F 2) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl] urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2p- toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration. [less ▲]

Development of a fluorescent microplate cell based assay for the rapid evaluation of human thromboxane A2 receptor modulators acting on α and β isoforms

Poster (2006, August)

Pharmacological evaluation of TP receptor antagonists characterized by differential activity on alpha and beta isoforms

Poster (2006, July)

Conception, synthèse et évaluation biologique de composés coumariniques en tant qu’agents anti-cancéreux et anti-angiogéniques potentiels

Poster (2006, June)

Nouveaux développements dans le domaine des analogues pyridiniques du nimésulide présentant un pont « inter-cycle » aminé

Poster (2006, June)

Evaluation pharmacologique d'une série de composés nitrobenzéniques sur les deux isoformes du récepteur au thromboxane A2, TPα et TPβ

Poster (2006, June)

Application de la LC-SPE-RMN et de la LC-MS à la détermination structurale des métabolites d’activateurs des canaux KATP de la classe des 3-alkylamino-4H-arylthiadiazine 1,1-dioxydes

Poster (2006, June)

Application of LC-SPE-NMR and LC-Q-TOF MS/MS to the structural determination of KATP channel openers metabolites belonging to the 3-alkylamino-4H-1,2,4-arylthiadiazine 1,1-dioxides

Poster (2006, May 17)

From the design to the clinical application of thromboxane modulators

in Current Pharmaceutical Design (2006), 12(8), 903-923

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of ... [more ▼]

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H-2 (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several Compounds have been launched on the market and others are tinder clinical evaluation. In the first part of this review. we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part. we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock.. preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis. [less ▲]

The use of nimesulide and its analogues in cancer chemoprevention

in Anti-Cancer Agents in Medicinal Chemistry (2006), 6