SYNTHESIS AND PHARMACOLOGY OF PYRID-3-YL SULFONYLUREAS AND THIOUREAS AS ASTROCYTIC NA-K+ COTRANSPORTER INHIBITORS(2CL)

The pharmacology of lipophilic 4-arylamino- and 4-cycloalkylaminopyrid -3-ylsulfonyl(thio)ureas and their synthesis designed from torasemide are described. These compounds could lead to a method of inhibiting th e astrocytic Na+ 2Cl(-) K+ cotransporter and thus treating cerebral ed ema. Their lipophilicity and ionization constants were determined. Sev en lipophilic compounds (17, 18, 22, 23, 24, 32 and 36) exhibited a hi gh inhibitory potency (IC50 < 10 mu M) and had lost the diuretic prope rties of torasemide. One of them, eptylamino)pyrid-3-yl]sulfonyl)-N'-c ycloheptylurea 17 (0.1-1 mg/kg) was found to increase the gasp delay i n hypoxia-exposed mice. In preliminary experiments, 17 (1-2.5 mg/kg) s trongly reduced the morbidity and mortality rate of gerbils after perm anent left carotid artery ligation. In-vitro experiments confirmed its antiedematous activity.