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) zenesulfonyl] urea (14) was drawn from two thromboxane A(2) receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A(2) (TXA(2)) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 muM) With an IC50 value of 0.45 and 0.15 muM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA(2) agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14(1 muM) completely inhibited TXA(2) 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 TXA(2) antagonists related to torasemide and their receptor.