Studies no Nonpeptide Angiotensin II Receptor Antagonists. I. Synthesis and Biological Evaluation of Pyrazolo[1, 5-b][1, 2, 4]triazole Derivatives with Alkyl Substituents

Abstract

Alkyl-substituted pyrazolo[1, 5-b][1, 2, 4]triazole derivatives were synthesized and evaluated for activity as angiotensin II receptor antagonists. Molecules with the (methylbiphenyly)tetrazole moiety at N-5 were the preferred compounds. Ethyl substitutions a both C-2 and C-7 resulted in the optimal compound, 2, 7-diethyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1, 5-b][1, 2, 4]triazole (5n), with a pA₂ value of 8.74 in rabbit aorta. In the in vivo tests, 5n inhibited the angiotensin II-induced pressor response in rats after oral administration. This compound also produced a dose-dependent decrease in blood pressure when administered orally to conscious furosemide-treated dogs, having a longer duration of action as compared to DuP 753. These data suggest that 5n may be a useful agent for the treatment of angiotensin II-dependent disease, such as hypertension.