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Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.

ABSTRACT: γ-Secretase (GS) is a key target for the potential treatment of Alzheimer's disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) (S)-3 (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in vitro and in vivo DMPK profile. Furthermore, based on its in vivo efficacy in a pharmacodynamic mouse model and the outcome of the dose range finding (DRF) toxicological studies in two species, this compound was selected to undergo entry in human enabling studies (e.g., GLP toxicology and scale up activities).

SUBMITTER: Ratni H

PROVIDER: S-EPMC7294721 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.

Ratni Hasane H Alker Andre A Bartels Bjoern B Bissantz Caterina C Chen Weichun W Gerlach Irene I Limberg Anja A Lu Mingqiu M Neidhart Werner W Pichereau Solen S Reutlinger Michael M Rodriguez-Sarmiento Rosa-Maria RM Jakob-Roetne Roland R Schmitt Georg G Zhang Eric E Baumann Karlheinz K

ACS medicinal chemistry letters 20200427 6

γ-Secretase (GS) is a key target for the potential treatment of Alzheimer's disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) (<i>S</i>)-<b>3</b> (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in vitro and in vivo DMPK profile. Furthermore, based on its in vivo effic ...[more]

PMID: 32551009

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Project description:IntroductionAlzheimer's disease brains are characterized by extracellular plaques containing the aggregated amyloid β42 (Aβ42) peptide and intraneuronal tangles containing hyperphosphorylated tau. Aβ42 is produced by sequential processing of the amyloid precursor protein (APP) by β-secretase followed by γ-secretase. Substantial efforts have been put into developing pharmaceuticals preventing the production or increasing the clearance of Aβ42. However, treatments inhibiting γ-secretase have proven disappointing due to off-target effects. To circumvent these effects, γ-secretase modulators (GSMs) have been developed, which rather than inhibiting γ-secretase shift its preference into producing less aggregation-prone shorter Aβ peptides. Belonging to the same family of proteins as APP, amyloid-like protein 1 (APLP1) is also a substrate for γ-secretase. Herein we investigated whether the GSM E2012 affects APLP1 processing in the central nervous system by measuring APLP1 peptide levels in cerebrospinal fluid (CSF) before and after E2012 treatment in dogs.MethodsAn in-house monoclonal APLP1 antibody, AP1, was produced and utilized for immunopurification of APLP1 from human and dog CSF in a hybrid immuno-affinity mass spectrometric method. Seven dogs received a single dose of 20 or 80 mg/kg of E2012 in a randomized cross-over design and CSF was collected prior to and 4, 8 and 24 hours after dosing.ResultsWe have identified 14 CSF APLP1 peptides in humans and 12 CSF APLP1 peptides in dogs. Of these, seven were reproducibly detectable in dogs who received E2012. We found a dose-dependent relative increase of the CSF peptides APLP1β17, 1β18 and 1β28 accompanied with a decrease of 1β25 and 1β27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection.ConclusionWe show an in vivo effect of the GSM E2012 on the processing of APLP1 which is measurable in CSF. These data suggest that APLP1 peptides may be used as biomarkers to monitor drug effects of GSMs on γ-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.

Dataset Information

Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.

Publications

Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.

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