STUDIES ON NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - I - SYNTHESIS AND BIOLOGICAL EVALUATION OF PYRAZOLO[1,5-B][1,2,4]TRIAZOLE DERIVATIVES WITH ALKYL SUBSTITUENTS

Alkyl-substituted pyrazolo [1,5-b][1,2,4]triazole derivatives were syn thesized and evaluated for activity as angiotensin II receptor antagon ists. Molecules with the (methylbiphenylyl)tetrazole moiety at N-5 wer e the preferred compounds. Ethyl substitutions at both C-2 and C-7 res ulted in the optimal compound, ,7-diethyl-5-[[2'-(1H-tetrazol-5-yl)bip henyl-4-yl] methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (5n), with a pA( 2) value of 8.74 in rabbit aorta. In the in vivo tests, 5n inhibited t he angiotensin II-induced presser response in rats after oral administ ration. This compound also produced a dose-dependent decrease in blood pressure when administered orally to conscious furosemide-treated dog s, having a longer duration of action as compared to DuP 753. These da ta suggest that 5n may be a useful agent for the treatment of angioten sin II-dependent disease, such as hypertension.