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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Authors: | Shimada Yoshiaki Akane Hiroaki Taniguchi Nobuaki Matsuhisa Akira Kawano Noriyuki Kikuchi Kazumi Yatsu Takeyuki Tahara Atsuo Tomura Yuichi Kusayama Toshiyuki Wada Koh-ichi Tsukada Junko Tsunoda Takashi Tanaka Akihiro |
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Institution: | Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. shimada@yamanouchi.co.jp |
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Abstract: | 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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