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 AT1 receptor (IC50 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 N1. These compounds were available in highly regioselective fashion via condensation of a substituted hydrazine hydrochloride with a 2-(methoxyimino)-4-oxoalkanoate intermediate. In vitro, the most potent pyrazolecarboxylic acids had n-butyl at C3 and were substituted at N1 by such groups as 2,6-dichlorophenyl (19h), 2-(trifluoromethyl)phenyl (19k), benzyl (19t), and phenethyl (19u), all with IC50 values of 0.18-0.24 nM. Although less potent in the receptor assay, 3-n-propylpyrazolecarboxylic acids were at least as effective as their butyl counterparts in vivo. Several of the pyrazolecarboxylic acid derivatives demonstrated potent, long-lasting oral activity in rats. At 1 mg/kg po, the 1-benzyl-3-butyl (19t), 1-(2,6-dichlorophenyl)-3-propyl (19v), 3-propyl-1-(2,2,2-trifluoroethyl) (19y), and 1-benzyl-3-propyl (19z) analogues all gave greater-than-or-equal-to 75 % inhibition of the All pressor response in the rat model, with duration of action greater-than-or-equal-to 23 h.