Design, synthesis and biological evaluation of a sulfonylcyanoguanidine asthromboxane A(2) 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 antag onists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A(2) (TXA(2)) receptor of human washed platel ets. 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, resp ectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trache a 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) s ynthase of human platelets. The pK(a) value and the crystallographic data o f 14 were determined and used to propose an interaction model between the T XA(2) antagonists related to torasemide and their receptor.