Design,synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease |
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Authors: | Toda Narihiro Tago Keiko Marumoto Shinji Takami Kazuko Ori Mayuko Yamada Naho Koyama Kazuo Naruto Shunji Abe Kazumi Yamazaki Reina Hara Takao Aoyagi Atsushi Abe Yasuyuki Kaneko Tsugio Kogen Hiroshi |
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Institution: | Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. |
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Abstract: | We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration. |
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