Brain Penetration Optimization and Anti-neuroinflammation Evaluation of Potent 6-Methyl-7-azaindol-3-yl-quinazoline DYRK1A Inhibitors for Alzheimer’s Disease

Abstract Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) to regulate microglia-mediated neuroinflammation represents a promising therapeutic strategy for Alzheimer’s disease (AD). To address the limited brain penetration of our earlier lead ZJCK-6-46, an intramolecular cyclization strategy was employed to mask the HBD ability of the P-gp efflux-prone amino and hydroxyl groups in the (S)-2-amino-2-phenylethanol moiety, facilitating comprehensive optimization of physicochemical properties. This effort yielded a more promising candidate, ZJCK-6-72, which maintained the overall kinase selectivity profile despite a 13.5-fold DYRK1A potency reduction and exhibited marked anti-neuroinflammatory activity and lower microglial cytotoxicity. Notably, ZJCK-6-72 showed significantly reduced P-gp efflux liability, and its improved oral absorption and brain penetration synergistically enhanced brain exposure in vivo, which translated into robust efficacy in both LPS-induced and 5×FAD transgenic mouse models. This work provides valuable insights for advancing DYRK1A-targeted AD therapies and establishes a viable paradigm for optimizing brain penetration in CNS drug discovery.