Nonpeptide Arginine Vasopressin Antagonists for Both V_<1A> and V_2 Receptors : Synthesis and Pharmacological Properties of 4'-[5-(Substituted Methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]benzanilide and 4'-[5-(Substituted Methyl)-2,3-dihy

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概要

• 論文の詳細を見る

• Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V_<1A> and V_2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V_<1A> and V_2 receptors based on the hypothesis that the blockade of both V_<1A> and V_2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V_<1A> and V_2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinitiy compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinitiy and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V_<1A> and V_2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.

• 公益社団法人日本薬学会の論文
• 1999-03-15

著者

• TANAKA Akihiro

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

• Tanaka A

  Faculty Of Pharmaceutical Sciences Tokyo University Of Science

• Tanaka A

  Yamanouchi U.k. Ltd. Surrey Gbr

• 増田 明

  富山医科薬科大学麻酔科

• MATSUHISA Akira

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

• KIKUCHI Kazumi

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

• YATSU Takeyuki

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

• Kikuchi Kazumi

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Yatsu Takeyuki

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Matsuhisa Akira

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Matsuhisa Akira

  Gastrointestinal Research Laboratories Institute For Drug Discovery Research Yamanouchi Pharmaceutic

• Tanaka Akihiro

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• SAKAMOTO Kenichiro

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

• Yatsu Takeyuki

  Astellas Pharma Inc. Ibaraki Jpn

• Tahara Atsuo

  Drug Discovery Research Astellas Pharma Inc.

• Sakamoto K

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Matsuhisa Akira

  Institute For Drug Discovery Research Astellas Pharma Inc.

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