In LaFerla 3xTg-C57BL6 mice, the increase in hyperphosphorylated Tau (pTau) is replicated, making them a viable in vivo model for Alzheimer’s disease research. Oral administration of GSK-3β inhibitor 2 at 30 mg/kg in a nanosuspension form to LaFerla 3xTg-C57BL6 male mice significantly decreases pTau396 levels. However, GSK-3β inhibitor 2 demonstrates only limited brain penetration (B/P = 0.26), assessed at a single time point^[1].

GSK-3β inhibitor 2's pyridine carboxamide forms hydrogen bonds with the V135 backbone amide hinge, and its thiazolyl primary amide's carbonyl oxygen establishes a key hydrogen bond with K85. The electron density quality of the methoxy moiety's methyl group in GSK-3β inhibitor 2 doesn't clearly define its position in the model. However, a single crystal X-ray diffraction method confirmed intramolecular hydrogen bonding between the methoxy -O- and the amide N-H in GSK-3β inhibitor 2^[1].