Interrupted Polonovski Strategy for the Synthesis of Functionalized Amino Acids and Peptides.

The α-functionalization of carbamate-protected hydroxylamine glycine derivatives, acting as imine surrogates via an interrupted Polonovski reaction, is described to access functionalized amino acid derivatives. The addition of C, N, O, and S nucleophiles was achieved in a one-pot procedure in 37% to 92% yield. This method could be extended to dipeptide derivatives for the functionalization of both the C-terminus and N-terminus.

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.