Development of Potent Serotonin-3(5-HT_3) Receptor Antagonists. II. Structure-Activity Relationships of N-(1-Benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)carboxamides

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概要

• 論文の詳細を見る

• Our studies on 4-amino-5-chloro-2-ethoxybenzamides led to the discovery that the N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)benzamide 9 and the 1-benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 10 are potent serotonin-3 (5-HT_3) receptor antagonists. Structure-activity relationship (SAR) studies on the influence of the aromatic nucleus of 9 and 10 upon inhibition of the von Bezold-Jarisch reflex in rats are described. Heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridazine, 1,2-benzisoxazole, indole, quinoline, and isoquinoline rings showed weak 5-HT_3 receptor antagonistic activity. Within this series, use of the 1H-indazole ring as an aromatic moiety led to a substantial increase of the acitivity; the 1H-indazolylcarboxamides 54,57,97,and 102 showed potent 5-HT_3 receptor antagonistic activity. The optimal compound identified via extensive SAR studies was N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (54), whose effect was superior to that of the corresponding benzamide 10 and essentially equipotent to those of ondansetron (1) and granisetron (4).

• 社団法人日本薬学会の論文
• 1995-11-15

著者

• 原田 博史

  Dainippon Pharmaceutical Co. Ltd.

• 森江 俊哉

  Dainippon Pharmaceutical Co., Ltd.,

• 広川 美視

  Dainippon Pharmaceutical Co., Ltd.,

• 寺内 英夫

  Dainippon Pharmaceutical Co., Ltd.,

• 藤原 巖

  Dainippon Pharmaceutical Co., Ltd.,

• 吉田 直之

  Dainippon Pharmaceutical Co., Ltd.,

• 賀登 志朗

  Dainippon Pharmaceutical Co., Ltd.,

• 森江 俊哉

  大日本製薬株式会社創薬研究所

• 吉田 直之

  大日本製薬(株)薬理研究所

• Kato Satoru

  Kanazawa Univ. Kanazawa Jpn

• 賀登 志朗

  大日本製薬株式会社創薬研究所

• Yoshida Naoko

  Institute For Medical And Dental Engineering Tokyo Medical And Dental University

• Kato S

  Discovery Research Laboratories I Dainippon Pharmaceutical Co. Ltd.

• Kato S

  Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• 吉田 直之

  大日本製薬株式会社創薬研究所第一薬理研究部

• Yoshida Naotoshi

  Medicinal Plant Garden Faculty Of Pharmaceutical Sciences Hokkaido University

• 吉田 直之

  大日本製薬株式会社創薬研究所

• 藤原 巖

  大日本製薬株式会社創薬研究所

• 広川 美視

  Dainippon Pharmaceutical Co. Ltd.

• Harada H

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• 寺内 英夫

  Dainippon Pharmaceutical Co. Ltd.

• Hirokawa Y

  Medicinal Chemistry Group Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• Kato Satoru

  Department Of Molecular Neurobiology Graduate School Of Medicine University Of Kanazawa

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