Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A₂ receptor antagonist and thromboxane synthase inhibitor

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 μM) with an IC50 value of 0.45 and 0.15 μM, 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 μM) completely inhibited TXA₂ synthase of human platelets. The pK_a 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.