Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to char-acterize the antiangiogenic properties of a series of original dual thromboxane A2 (TXA2) inhibitors derived from torasemide, a marketed loop diuretic with TXA2 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 TXA2 receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA2 receptor ag-onist, and inhibited platelet TXA2 synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA2 inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelia