Tuning Brain Penetration in DYRK1A Inhibitors for Alzheimer's Neuroinflammation
- Builds on a prior azaindole-quinazoline lead compound and addresses its limited blood-brain barrier penetration.
- Uses an intramolecular cyclization strategy to mask a hydrogen-bond-donating amine group that was prone to P-glycoprotein-mediated efflux.
- Resulting analogs retain strong DYRK1A inhibitory activity while markedly improving brain exposure.
- Optimized compounds reduce microglia-driven neuroinflammatory markers in disease-relevant models.
💡 Points
Masking an H-bond donor by intramolecular cyclization to dodge P-gp is a well-worn CNS trick, but pulling it off on an azaindole-quinazoline kinase core without bleeding DYRK1A potency is the part most efflux-liability campaigns fail at. If the microglial neuroinflammation readout replicates in a second model, this is a genuinely reusable template for other P-gp-limited kinase programs.