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

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概要

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• 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.

• 公益社団法人日本薬学会の論文
• 1998-06-15

著者

• FUJIMORI Akira

  Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.

• 渡辺 敏子

  School Of Pharmaceutical Sciences Toho University

• Okazaki T

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Okazaki Toshio

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Fujimori Akira

  アステラス製薬研究本部薬理研究所

• Fujimori Akira

  Applied Pharmacology Research Laboratories Drug Discovery Research Astellas Pharma Inc.

• Watanabe Toshifumi

  Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries

• Yanagisawa I

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Yanagisawa Isao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Yanagisawa Isao

  山之内製薬

• Fujimori Akira

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Watanabe T

  Chiba Univ. Chiba Jpn

• KIKUCHI Kazumi

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Kikuchi Kazumi

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Watanabe Toshiko

  Faculty Of Pharmaceutical Sciences Chiba University

• Watanabe Toshiko

  Graduate School Of Pharmaceutical Sciences Chiba University

• Watanabe Toshihiro

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Shibasaki Masayuki

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Shibasaki Masayuki

  General Education Courses Faculty Of Engineering Toyo University

• Kikuchi K

  Graduate School Of Pharmaceutical Sciences The University Of Tokyo:presto Jst Corporation

• Inagaki Osamu

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Fujimori Akira

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• SUGA Akira

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• Suga Akira

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

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