Activity of a novel dual thromboxane A2receptor antagonist and thromboxane synthase inhibitor (BM-573) on platelet function and isolated smooth muscles

The pharmacomodulation of sulfonylureas structurally related to torasemide and characterized by a TXA2antagonism led to the synthesis of BM-573. This original molecule showed a high affinity (IC501.3 nM) for the TXA2receptor of human platelets in comparison with both reference compounds, SQ-29548 (IC5021 nM) and sulotroban (IC50930 nM). Moreover, this torasemide derivative was found to be a potent inhibitor of human platelet aggregation induced by arachidonic acid (ED100=0.13 μM) or by U-46619 (ED50=0.24 μM), a TXA2agonist. BM-573 relaxed the isolated rat thoracic aorta (ED50=28.4 nM) and guinea-pig trachea (ED50=17.7 nM) contracted by U-46619. BM-573 (1 μM) completely reduced the platelet production of TXB2induced by arachidonic acid. Finally, BM-573 (30 mg/kg, per os) lost the diuretic properties of torasemide in rats.