Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.
Identifieur interne : 000887 ( France/Analysis ); précédent : 000886; suivant : 000888Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.
Auteurs : Pierre Bohn [France] ; Nicolas Le Fur [France] ; Guillaume Hagues [France] ; Jean Costentin [France] ; Nicolas Torquet [France] ; Cyril Papamicaël [France] ; Francis Marsais [France] ; Vincent Levacher [France]Source :
- Organic and Biomolecular Chemistry [ 1477-0520 ] ; 2009-06-21.
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.
Url:
DOI: 10.1039/b903041g
Affiliations:
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Hal:inserm-00467214Le document en format XML
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76821 Mont-Saint-Aignan</addrLine><country key="FR"></country></address><ref type="url">http://www.univ-rouen.fr/</ref></desc></org></tutelle><tutelle active="#struct-301288" type="direct"><org type="department" xml:id="struct-301288" status="VALID"><orgName>Institut National des Sciences Appliquées - Rouen</orgName><orgName type="acronym">INSA Rouen</orgName><desc><address><country key="FR"></country></address></desc><listRelation><relation active="#struct-301232" type="direct"></relation></listRelation></org></tutelle><tutelle active="#struct-301232" type="indirect"><org type="institution" xml:id="struct-301232" status="VALID"><orgName>Institut National des Sciences Appliquées</orgName><orgName type="acronym">INSA</orgName><desc><address><country key="FR"></country></address></desc></org></tutelle></tutelles></hal:affiliation><country>France</country><placeName><settlement type="city">Le Havre</settlement><region type="region" nuts="2">Région Normandie</region><region type="old region" nuts="2">Haute-Normandie</region></placeName><orgName type="university">Université du Havre</orgName><placeName><settlement type="city">Rouen</settlement><region type="region" nuts="2">Région Normandie</region><region type="old region" nuts="2">Haute-Normandie</region></placeName><orgName type="university">Université de Rouen</orgName></affiliation></author></analytic><idno type="DOI">10.1039/b903041g</idno><series><title level="j">Organic and Biomolecular Chemistry</title><idno type="ISSN">1477-0520</idno><imprint><date type="datePub">2009-06-21</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Haute-Normandie</li><li>Région Normandie</li></region><settlement><li>Le Havre</li><li>Rouen</li></settlement><orgName><li>Université de Rouen</li><li>Université du Havre</li></orgName></list><tree><country name="France"><region name="Région Normandie"><name sortKey="Bohn, Pierre" sort="Bohn, Pierre" uniqKey="Bohn P" first="Pierre" last="Bohn">Pierre Bohn</name></region><name sortKey="Costentin, Jean" sort="Costentin, Jean" uniqKey="Costentin J" first="Jean" last="Costentin">Jean Costentin</name><name sortKey="Hagues, Guillaume" sort="Hagues, Guillaume" uniqKey="Hagues G" first="Guillaume" last="Hagues">Guillaume Hagues</name><name sortKey="Le Fur, Nicolas" sort="Le Fur, Nicolas" uniqKey="Le Fur N" first="Nicolas" last="Le Fur">Nicolas Le Fur</name><name sortKey="Levacher, Vincent" sort="Levacher, Vincent" uniqKey="Levacher V" first="Vincent" last="Levacher">Vincent Levacher</name><name sortKey="Marsais, Francis" sort="Marsais, Francis" uniqKey="Marsais F" first="Francis" last="Marsais">Francis Marsais</name><name sortKey="Papamicael, Cyril" sort="Papamicael, Cyril" uniqKey="Papamicael C" first="Cyril" last="Papamicaël">Cyril Papamicaël</name><name sortKey="Torquet, Nicolas" sort="Torquet, Nicolas" uniqKey="Torquet N" first="Nicolas" last="Torquet">Nicolas Torquet</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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