Compound 39a(Northeastern University)

Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Glycogen synthase kinase 3β (GSK3β), a key enzyme in tau phosphorylation, is a promising therapeutic target for AD. Herein, we employed a structure-based drug design strategy to develop a novel series of harmine derivatives as potent GSK3β inhibitors. Among them, compound 39a bearing an intramolecular hydrogen bond scaffold, showed potent GSK3β inhibition (IC₅₀ = 0.37 nM), meanwhile maintaining remarkable kinase selectivity, including >25000-fold selectivity over dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a well-known target of β-carboline derivative harmine. It suppressed tau phosphorylation in Tau (P301L) 293T cells (EC₅₀ = 0.06 ± 0.01 μM) and exhibited favorable blood-brain barrier permeability. Notably, 39a significantly attenuated cognitive deficits and tau hyperphosphorylation pathology in OA-induced C57BL/6J mice and 3 × Tg-AD mouse models, without causing spontaneous locomotor defects at therapeutic doses. Collectively, 39a emerges as a promising GSK3β inhibitor for probing GSK3β's role in AD pathogenesis and guiding anti-AD drug discovery.