Studies on Nonpeptide Angiotensin II Receptor Antagonists. IV. Synthesis and Biological Evaluation of 4-Acrylamide-1H-imidazole Derivatives

A novel series of nonpeptide angiotensin II antagonists containing the acrylamide group at the 4-position of the imidazole ring was synthesized and their antagonistic activity was examined by functional assay in rabbit aorta.The acrylamide group was selected as a large lipophilic surrogate for the chloro group of EXP3174. A structure-activity relationship study of the acrylamide moiety has shown that substitution at the 4-position with the N-methyl-3, 3-dimethylacrylamide group resulted in the optimal compound, 2-butyl-4-[(3, 3-dimethylacryloyl)methyl-amino]-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (1), which was superior to EXP3174 in vitro. Since 1 showed only poor activity against angiotensin II-induced pressor response in rats after oral administration, the carboxylic acid function of 1 was converted into prodrug esters (13). Among these, the 1-[(ethoxycarbonyl)oxy]ethyl ester (13a) showed the most potent and longest-lasting activity when given orally to rats. When administered orally to conscious furosemide-treated dogs, 13a showed an approximately-3-fold increased hypotensive activity in comparison with DuP 753. These data suggest that 13a may be an useful agent for the treatment of angiotensin II-dependent diseases, such as hypertension.