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 synthesi zed and their antagonistic activity was examined by functional assay i n rabbit aorta. The acrylamide group was selected as a large lipophili c surrogate for the chloro group of EXP3174. A structure-activity rela tionship study of the acrylamide moiety has shown that substitution at the 4-position with the N-methyl-3,3-dimethylacrylamide group resulte d in the optimal compound, yl)biphenyl-4-yl]methyl]-1H-imidazole-5-car boxylic acid (1), which was superior to EXP3174 in vitro. Since 1 show ed only poor activity against angiotensin II-induced presser response in rats after oral administration, the carboxylic acid function of 1 w as converted into prodrug esters (13). Among these, the 1-[(ethoxycarb onyl)oxy]ethyl ester (13a) showed the most potent and longest-lasting activity when given orally to rats. When administered orally to consci ous furosemide-treated dogs, 13a showed an approximately 3-fold increa sed hypotensive activity in comparison with DuP 753. These data sugges t that 13a may be an useful agent for the treatment of angiotensin II- dependent diseases, such as hypertension.