Nonpeptide angiotensin II antagonists derived from 1H-pyrazole-5-carboxylates and 4-aryl-1H-imidazole-5-carboxylates.

Two series of potential angiotensin II antagonists derived from carboxyl-functionalized «diazole» heterocycles have been prepared and evaluated. Initially, a limited investigation of 4-arylimidazole-5-carboxylates led to 2-n-butyl-4-(2-chlorophenyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]1H-imidazole-5-carboxylic acid (12b), which was found to be a highly potent antagonist of the rabbit aorta AT 1 receptor (IC 50 0.55 nM). In conscious, normotensive rats, 12b at 0.1 mg/kg iv inhibited the pressor response to AII by 88%, with a duration of >6 h. More extensively studied was an isosteric series of 3-alkyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylates bearing aryl, alkyl, or aralkyl substituents at N 1