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Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

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    Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors
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    Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 du CNRS, Université Louis Pasteur, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch Cedex, France, and Institut für Pharmazeutische Chemie, Heinrich-Heine-Universität, Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2001, 44, 17, 2707–2718
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    https://doi.org/10.1021/jm001088u
    Published July 20, 2001
    Copyright © 2001 American Chemical Society
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    Starting from the 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazine 1, we performed the design, the synthesis, and the structure−activity relationships of a series of pyridazine analogues acting as AChE inhibitors. Structural modifications were achieved on four different parts of compound 1 and led to the following observations:  (i) introduction of a lipophilic environment in the C-5 position of the pyridazine ring is favorable for the AChE-inhibitory activity and the AChE/BuChE selectivity; (ii) substitution and various replacements of the C-6 phenyl group are possible and led to equivalent or slightly more active derivatives; (iii) isosteric replacements or modifications of the benzylpiperidine moiety are detrimental to the activity. Among all derivatives prepared, the indenopyridazine derivative 4g was found to be the more potent inhibitor with an IC50 of 10 nM on electric eel AChE. Compared to compound 1, this represents a 12-fold increase in potency. Moreover, 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-5-methyl-6-phenylpyridazine 4c, which showed an IC50 of 21 nM, is 100-times more selective for human AChE (human BuChE/AChE ratio of 24) than the reference compound tacrine.

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    †

     Université Louis Pasteur.

    ‡

     Heinrich-Heine-Universität.

    *

     Address correspondence to Prof. C. G. Wermuth. Tel:  +33 388 67 37 22. Fax:  +33 388 67 47 94. E-mail:  [email protected].

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    Cite this: J. Med. Chem. 2001, 44, 17, 2707–2718
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    Published July 20, 2001
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