Substituted 2-oxo-azepane derivatives are potent, orally active γ-secretase inhibitors

A hydroxamic acid screening hit was elaborated to 5,5-difluoro-2-oxoazepane derivatives exhibiting low nanomolar inhibition of γ-secretase, a key proteolytic enzyme involved in Alzheimer’s disease (AD). Oral activity was observed in a transgenic mouse model for AD. A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of γ-secretase, a key proteolytic enzyme involved in Alzheimer’s disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure–activity relationship are discussed and in vivo active compounds are presented.