Preparation of non-peptide,highly potent and selective antagonists of arginine vasopressin V1A receptor by introduction of alkoxy groups |
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Authors: | Shimada Yoshiaki Taniguchi Nobuaki Matsuhisa Akira Yatsu Takeyuki Tahara Atsuo 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: | A series of compounds structurally related to 4'-(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2'-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V1A receptors. Consequently, we found that the (Z)-4'-(4,4-Difluoro-5-(4-dimethylaminopiperidino)carbonylmethylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl]carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4'-(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper. |
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