Discovery of a Novel and Brain-Penetrant O-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Enzymology

Background:

• O-GlcNAcase (OGA) is implicated in tau-mediated neurodegenerative disorders.
• Understanding OGA's role requires potent chemical tools with good pharmacokinetics.
• Current knowledge of OGA's function in these pathologies is limited.

Purpose of the Study:

• To discover and characterize novel OGA inhibitors.
• To develop chemical probes for studying OGA in neurodegenerative diseases.
• To validate OGA as a therapeutic target for tauopathies.

Main Methods:

• Virtual screening (structure-based and ligand-based) combined with optimization.
• Synthesis and characterization of novel aminopyrimidine-based compounds.
• In vitro assays to assess OGA inhibition and cellular effects; pharmacokinetic studies and crystallography.

Main Results:

• Discovery of compound 5i, a potent OGA inhibitor with an aminopyrimidine scaffold.
• Compound 5i increased O-GlcNAcylated protein levels in cells.
• Demonstrated favorable pharmacokinetics, brain permeability, and high affinity for OGA via hydrophobic interactions.

Conclusions:

• Compound 5i is a novel, potent OGA inhibitor with suitable drug-like properties.
• This inhibitor can serve as a valuable chemical probe for OGA research.
• Findings support the therapeutic potential of OGA inhibition in treating tauopathies.