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

Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid beta peptides (A beta) is central to Alzheimer's disease (AD) etiology. A beta peptides are produced by sequential cleavage of APP by beta-secretase (BACE-1) and gamma-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit A beta 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 A beta 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 beta-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on A beta peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect beta-secretase inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.