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Author Gay, Marion ♦ Evrard, Caroline ♦ Descamps, Florian ♦ Carato, Pascal ♦ Renault, Nicolas ♦ Coevoet, Mathilde ♦ Eddarkaoui, Sabiha ♦ Baud, Catherine ♦ Larchanché, Paul-Emmanuel ♦ Buée, Luc ♦ Bakali, Jamal El ♦ Vingtdeux, Valérie ♦ Sergeant, Nicolas ♦ Melnyk, Patricia
Source Hyper Articles en Ligne (HAL)
Content type Text
Publisher Elsevier
File Format PDF
Language English
Subject Keyword chim ♦ sdv ♦ Chemical Sciences/Medicinal Chemistry ♦ Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
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.
ISSN 02235234
Educational Use Research
Learning Resource Type Article
Publisher Date 2018-01-01
e-ISSN 17683254
Journal European Journal of Medicinal Chemistry
Volume Number 159
Page Count 22
Starting Page 104
Ending Page 125