Preparation of Highly Potent and Selective Non-Peptide Antagonists of the Arginine Vasopressin V1A Receptor by Introduction of a 2-Ethyl-1H-1-imidazolyl Group

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  • Shimada Yoshiaki
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Akane Hiroaki
    Clinical Development Department, Yamanouchi Pharmaceutical Co., Ltd.
  • Taniguchi Nobuaki
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Matsuhisa Akira
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Kawano Noriyuki
    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.
  • Tahara Atsuo
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Tomura Yuichi
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Kusayama Toshiyuki
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Wada Koh-ichi
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Tsukada Junko
    Clinical Development Department, Yamanouchi Pharmaceutical Co., Ltd.
  • Tsunoda Takashi
    Chemical Technology Laboratory, Yamanouchi Pharmaceutical Co., Ltd.
  • Tanaka Akihiro
    Corporate Communications Department, Yamanouchi Pharmaceutical Co., Ltd.

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To find a new series of arginine vasopressin (AVP) V1A receptor antagonists, the influence of the 2-phenyl group of 2-phenyl-4′-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide (7) was investigated. Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V1A-selective compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further studies of these compounds were performed. Consequently, we found that the (Z)-4′-({4,4-difluoro-5-[(N-cyclopropylcarbamoyl)methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper

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