Title :

A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: toward a new profile of indirect ?-secretase inhibitors

Author(s) :

Gay, Marion [Auteur]
Evrard, Caroline [Auteur]
Descamps, Florian [Auteur]
Carato, Pascal [Auteur]
Renault, Nicolas [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Coevoet, Mathilde [Auteur]
Eddarkaoui, Sabiha [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Baud, Catherine [Auteur]
Larchanche, Paul-Emmanuel [Auteur]
Buee, Luc [Auteur]
El Bakali, Jamal [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Vingtdeux, Valerie [Auteur]
Sergeant, Nicolas [Auteur]
Melnyk, Patricia [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172

Journal title :

European Journal of Medicinal Chemistry

Abbreviated title :

Eur J Med Chem

Volume number :

159

Pages :

104-125

Publication date :

2018-09-22

ISSN :

1768-3254

English keyword(s) :

Lysosome
beta-secretase
BACE-1
Indirect inhibitor
Alzheimer's disease
Phenotypic
Amyloid precursor protein
Chloroquine
Autophagy

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid β peptides (Aβ) is central to Alzheimer's disease (AD) etiology. Aβ peptides are produced by sequential cleavage of APP ...
Show more >Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid β peptides (Aβ) is central to Alzheimer's disease (AD) etiology. Aβ peptides are produced by sequential cleavage of APP by β-secretase (BACE-1) and γ-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Aβ 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 Aβ 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 β-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on Aβ peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect β-secretase inhibitors.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
• Lille Neurosciences & Cognition (LilNCog) - U 1172

Submission date :

2024-01-30T10:27:29Z