Discovery of a Novel and Brain-Penetrant <i>O</i>-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization

O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a and novel OGA inhibitor, compound 5i, comprising aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining structure-based ligand-based approaches, followed sequential optimization focus ligand lipophilicity efficiency. This was observed increase level O-GlcNAcylated protein cells display suitable properties brain permeability. Crystallographic analysis revealed that series bind via characteristic hydrophobic interactions, which resulted high affinity moderate lipophilicity. Compound 5i could serve useful probe help establish proof-of-concept inhibition treatment tauopathies.