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-tetra zol-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.
Okazaki
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Watanabe
T
T
Kikuchi
K
K
Suga
A
A
Shibasaki
M
M
Fujimori
A
A
Inagaki
O
O
Yanagisawa
I
I
D000178:Acrylamides / Q000138:chemical synthesis*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D004039:Diet, Sodium-Restricted; D004195:Disease Models, Animal; D004232:Diuretics / Q000008:administration & dosage / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D005665:Furosemide / Q000008:administration & dosage / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C113404:1-((ethoxycarbonyl)oxy)ethyl 2-butyl-4-((3,3-dimethylacryloyl)methylamino)-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate; C113403:2-butyl-4-((3,3-dimethylacryloyl)methylamino)-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylic acid; D000178:Acrylamides; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D004232:Diuretics; D007093:Imidazoles; D011355:Prodrugs; D013777:Tetrazoles; D005665:Furosemide; C066026:losartan carboxylic acid; D019808:Losartan