Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer’s disease

• Glycogen synthase kinase 3 (GSK-3) is an important target for the treatment of Alzheimer’s disease.
• Reducing tau phosphorylation through GSK-3 inhibition has emerged as a target for drug development of AD.
• We have discovered novel GSK-3 inhibitors (C-7a, -7b) and demonstrated pharmacological validation.
• New GSK-3 inhibitors (C-7a, -7b) were interfered with Aβ oligomers-induced neuronal cell death and tau phosphorylation in vitro.
• C-7a has efficacy in reducing the level of tau phosphorylation and improving short-term memory in 3xTg-AD mice.

Glycogen synthase kinase-3 (GSK-3) is emerging as a prominent therapeutic target of Alzheimer’s disease (AD). A number of studies have been undertaken to develop GSK-3 inhibitors for clinical use. We report two novel GSK-3 inhibitors (C-7a and C-7b) showing good activity and pharmacokinetic (PK) profiles. IC50 of new GSK-3 inhibitors were in the range of 120–130 nM, and they effectively reduced the Aβ-oligomers induced neuronal toxicity. Also, new GSK-3 inhibitors decreased the phosphorylated tau at pThr231, pSer396, pThr181, and pSer202, and inhibited the GSK-3 activity against Aβ-oligomers induced neuronal cell toxicity. In B6;129-Psen1tm1Mpm Tg(APPSwe, tauP301L)1Lfa/Mmjax model of AD, oral administration of C-7a (20 mg/kg, 50 mg/kg) showed increased total arm entries and spontaneous alteration of Y-maze which was regarded as short-term memory. In particular, 50 mg/kg C-7a treated mice significantly decreased the level of phosphorylated tau (Ser396) in brain hippocampus. We suggest that new GSK-3 inhibitor (C-7a) is potential candidates for the treatment of AD.