Discovery of Orally Available and Brain Penetrant AEP Inhibitors

Alzheimer’s Disease (AD) is the most widespread
form of
dementia, with one of the pathological hallmarks being the formation
of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated
Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving
enzyme that generates aggregation-prone Tau fragments. Inhibition
of AEP to reduce the level of toxic Tau fragment formation could represent
a promising therapeutic strategy. Here, we report the first orthosteric,
selective, orally bioavailable, and brain penetrant inhibitors with
an irreversible binding mode. We outline the development of the series
starting from reversible molecules and demonstrate the link between
inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo.