A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: Toward a new profile of indirect β-secretase inhibitors
Identifieur interne : 000086 ( France/Analysis ); précédent : 000085; suivant : 000087A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: Toward a new profile of indirect β-secretase inhibitors
Auteurs : Marion Gay [France] ; Caroline Evrard [France] ; Florian Descamps [France] ; Pascal Carato [France] ; Nicolas Renault [France] ; Mathilde Coevoet [France] ; Sabiha Eddarkaoui [France] ; Catherine Baud [France] ; Paul-Emmanuel Larchanché [France] ; Luc Buée [France] ; Jamal El Bakali [France] ; Valérie Vingtdeux [France] ; Nicolas Sergeant [France] ; Patricia Melnyk [France]Source :
- European Journal of Medicinal Chemistry [ 0223-5234 ] ; 2018.
Abstract
Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid b peptides (Ab) is central to Alzheimer's disease (AD) etiology. Ab peptides are produced by sequential cleavage of APP by b-secretase (BACE-1) and g-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Ab peptide production. However, this effect is accompanied by an inhibition of lysosome-mediated degradation pathways. Following on from the promising activity of two series of APP metabolism modulators derived from CQ, we sought to develop new series of compounds that would retain the inhibitory effects on Ab production without altering lysosome functions. Herein, we applied a ligand-based pharmacophore modeling approach coupled with de novo design that led to the discovery of a series of biaryl compounds. Structure-activity relationship studies revealed that minor modifications like replacing a piperidine moiety of compound 30 by a cyclohexyl (compound 31) allowed for the identification of compounds with the desired profile. Further studies have demonstrated that compounds 30 and 31 act through an indirect mechanism to inhibit b-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on Ab peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect b-secretase inhibitors.
Url:
DOI: 10.1016/j.ejmech.2018.08.092
Affiliations:
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Hal:hal-02060447Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en">A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: Toward a new profile of indirect β-secretase inhibitors</title>
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<country>France</country>
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<author><name sortKey="Carato, Pascal" sort="Carato, Pascal" uniqKey="Carato P" first="Pascal" last="Carato">Pascal Carato</name>
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<orgName type="acronym">JPArc - U1172 Inserm</orgName>
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<country>France</country>
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<author><name sortKey="Renault, Nicolas" sort="Renault, Nicolas" uniqKey="Renault N" first="Nicolas" last="Renault">Nicolas Renault</name>
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<orgName>Université de Lille</orgName>
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</address>
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<author><name sortKey="Eddarkaoui, Sabiha" sort="Eddarkaoui, Sabiha" uniqKey="Eddarkaoui S" first="Sabiha" last="Eddarkaoui">Sabiha Eddarkaoui</name>
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<author><name sortKey="Melnyk, Patricia" sort="Melnyk, Patricia" uniqKey="Melnyk P" first="Patricia" last="Melnyk">Patricia Melnyk</name>
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<idno type="DOI">10.1016/j.ejmech.2018.08.092</idno>
<series><title level="j">European Journal of Medicinal Chemistry</title>
<idno type="ISSN">0223-5234</idno>
<imprint><date type="datePub">2018</date>
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<front><div type="abstract" xml:lang="en"> <p>Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid b peptides (Ab) is central to Alzheimer's disease (AD) etiology. Ab peptides are produced by sequential cleavage of APP by b-secretase (BACE-1) and g-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Ab peptide production. However, this effect is accompanied by an inhibition of lysosome-mediated degradation pathways. Following on from the promising activity of two series of APP metabolism modulators derived from CQ, we sought to develop new series of compounds that would retain the inhibitory effects on Ab production without altering lysosome functions. Herein, we applied a ligand-based pharmacophore modeling approach coupled with de novo design that led to the discovery of a series of biaryl compounds. Structure-activity relationship studies revealed that minor modifications like replacing a piperidine moiety of compound 30 by a cyclohexyl (compound 31) allowed for the identification of compounds with the desired profile. Further studies have demonstrated that compounds 30 and 31 act through an indirect mechanism to inhibit b-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on Ab peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect b-secretase inhibitors.</p>
</div>
</front>
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<affiliations><list><country><li>France</li>
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<name sortKey="Buee, Luc" sort="Buee, Luc" uniqKey="Buee L" first="Luc" last="Buée">Luc Buée</name>
<name sortKey="Carato, Pascal" sort="Carato, Pascal" uniqKey="Carato P" first="Pascal" last="Carato">Pascal Carato</name>
<name sortKey="Coevoet, Mathilde" sort="Coevoet, Mathilde" uniqKey="Coevoet M" first="Mathilde" last="Coevoet">Mathilde Coevoet</name>
<name sortKey="Descamps, Florian" sort="Descamps, Florian" uniqKey="Descamps F" first="Florian" last="Descamps">Florian Descamps</name>
<name sortKey="Eddarkaoui, Sabiha" sort="Eddarkaoui, Sabiha" uniqKey="Eddarkaoui S" first="Sabiha" last="Eddarkaoui">Sabiha Eddarkaoui</name>
<name sortKey="El Bakali, Jamal" sort="El Bakali, Jamal" uniqKey="El Bakali J" first="Jamal" last="El Bakali">Jamal El Bakali</name>
<name sortKey="Evrard, Caroline" sort="Evrard, Caroline" uniqKey="Evrard C" first="Caroline" last="Evrard">Caroline Evrard</name>
<name sortKey="Larchanche, Paul Emmanuel" sort="Larchanche, Paul Emmanuel" uniqKey="Larchanche P" first="Paul-Emmanuel" last="Larchanché">Paul-Emmanuel Larchanché</name>
<name sortKey="Melnyk, Patricia" sort="Melnyk, Patricia" uniqKey="Melnyk P" first="Patricia" last="Melnyk">Patricia Melnyk</name>
<name sortKey="Renault, Nicolas" sort="Renault, Nicolas" uniqKey="Renault N" first="Nicolas" last="Renault">Nicolas Renault</name>
<name sortKey="Sergeant, Nicolas" sort="Sergeant, Nicolas" uniqKey="Sergeant N" first="Nicolas" last="Sergeant">Nicolas Sergeant</name>
<name sortKey="Vingtdeux, Valerie" sort="Vingtdeux, Valerie" uniqKey="Vingtdeux V" first="Valérie" last="Vingtdeux">Valérie Vingtdeux</name>
</country>
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