Discovery of Orally Available and Brain Penetrant AEP Inhibitors
Daniela Krummenacher, Weiping He, Bernd Kuhn, Christian Schnider, Angélica Beurier, Virginie Brom, Thulase Sivasothy, Christine Marty, Andreas Tosstorff, David S. Hewings, Stefanie Mesch, Emmanuel Pinard, Mathis Brändlin, Remo Hochstrasser, Paul Westwood, Judith Rothe, Alexandra Kronenberger, Federica Morandi, Simon Gutbier, Angelika Schuler, Dominik Heer, Ludivine Esteves Gloria, Lisa Joedicke, M.G. Rudolph, Lutz Müller, Fiona Grüninger, Karlheinz Baumann, Senthilvelrajan Kaniyappan, Nenad Manevski, Björn Bartels
Abstract
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 .