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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).