Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.

Pierre Bohn 1 Nicolas Le Fur 1, 2 Guillaume Hagues 3 Jean Costentin 3 Nicolas Torquet 3 Cyril Papamicaël 1, 2 Francis Marsais 1, 2 Vincent Levacher 1, 2
1 LITIS - Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes
2 AHHBO - Asymétrie, hétérocycles, hétérochimie et bio-organique
3 Neuropsycho-pharmacologie expérimentale
Abstract : This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach.
Type de document :
Article dans une revue
Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2009, 7 (12), pp.2612-8. 〈10.1039/b903041g〉
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http://www.hal.inserm.fr/inserm-00467214
Contributeur : Céline Breton <>
Soumis le : vendredi 26 mars 2010 - 11:28:34
Dernière modification le : lundi 1 octobre 2018 - 09:58:08

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Pierre Bohn, Nicolas Le Fur, Guillaume Hagues, Jean Costentin, Nicolas Torquet, et al.. Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.. Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2009, 7 (12), pp.2612-8. 〈10.1039/b903041g〉. 〈inserm-00467214〉

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