Studies on Nonpeptide Angiotensin II Receptor Antagonists. II. Synthesis and Biological Evaluation of 5H-Pyrazolo[1,5-b][1,2,4]triazole Derivatives with a C-Linked Oxygen Functional Group at the 6-Position
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概要
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2,7-Diethyl-5H-pyrazolo[1,5-b][1,2,4]triazole derivatives were synthesized and evaluated for activity as angiotensin II receptor antagonists. Replacement of the C-6 hydrogen with C-linked oxygen functional groups led to derivatives with increased in vitro activities. Among these compounds, 2,7-diethyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylic acid (2d) showed potent, insurmountable antagonism, but had poor oral potency against angiotensin II-induced pressor response in rats. In order to improve the oral activity, the carboxylic acid function of 2d was converted into a double ester. This modification afforded (±)-1-[(ethoxycarbonyl)oxy]ethyl 2,7-diethyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylate (2f), which was orally active in rats, and produced a dose-dependent decrease in blood pressure when administered orally to conscious furosemide-treated dogs, with ca. 3-fold increased potency in comparison with the parent C-6 hydrogen compound.
- 公益社団法人日本薬学会の論文
- 1998-02-15
著者
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FUJIMORI Akira
Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
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渡辺 敏子
School Of Pharmaceutical Sciences Toho University
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Okazaki T
Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn
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Okazaki Toshio
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Fujimori Akira
アステラス製薬研究本部薬理研究所
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Fujimori Akira
Applied Pharmacology Research Laboratories Drug Discovery Research Astellas Pharma Inc.
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Watanabe Toshifumi
Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries
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KURIHARA Hiroyuki
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,
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Yanagisawa I
Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn
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Yanagisawa Isao
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.
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Yanagisawa Isao
山之内製薬
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Fujimori Akira
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Watanabe T
Chiba Univ. Chiba Jpn
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KIKUCHI Kazumi
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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Kikuchi Kazumi
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Watanabe Toshiko
Faculty Of Pharmaceutical Sciences Chiba University
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Watanabe Toshiko
Graduate School Of Pharmaceutical Sciences Chiba University
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Watanabe Toshihiro
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Shibasaki Masayuki
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.
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Shibasaki Masayuki
General Education Courses Faculty Of Engineering Toyo University
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Kurihara H
Graduate School Of Pharmaceutical Sciences Chiba University
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Kikuchi K
Graduate School Of Pharmaceutical Sciences The University Of Tokyo:presto Jst Corporation
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Inagaki Osamu
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.
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Fujimori Akira
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.
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SUGA Akira
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,
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YANAGISAWA Isao
(Present address)Corporate Planning Department, Yamanouchi Pharmaceutical Co., Ltd.,
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Suga Akira
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Kubota H
Chemistry Research Laboratories Astellas Pharmaceutical Inc.
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Kurihara H
Chemistry Research Laboratories Astellas Pharmaceutical Inc.
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