Tideglusib

2 years -80 in solvent

Oral gavage

Tideglusib is in Phase II clinical trials in patients with Alzheimer's Disease.

26% peg400 (Polyethylene Glycol 400), 15% Chremophor EL and water

Tideglusib irreversibly inhibits GSK-3, reduces tau phosphorylation, and prevents apoptotic death in human neuroblastoma cells and murineprimary neurons. [1] Tideglusib (2.5 uM) inhibits glutamate-induced glial activation as evidenced by decreased TNF-alpha and COX-2 expression in rat primary astrocyte or microglial cultures. Tideglusib (2.5 uM) also exerts a potent neuroprotective effect on cortical neurons from glutamate-induced excitotoxicity as evidenced by significant reduction in the number of Annexin-V-positive cells in rat primary astrocyte or microglial cultures. [2]

Binding Experiments with Radiolabeled Tideglusib, [35S]Tideglusib (207 Bq/nmol) at 55 uM is incubated with 5 uM GSK-3beta for 1 h at 25 C in 315 uL of 50 mM Tris-HCl, pH 7.5, containing 150 mM NaCl and 0.1 mM EGTA. The incubation is extended for another 30 min after having added 35 uL of the same buffer with or without 100 mM DTE. Finally, a third 40-uL aliquot of each original sample is mixed with 10 uL of denaturing electrophoresis sample buffer without reducing agents, and 35 uL of this mixture is loaded onto a 10% polyacrylamide gel and subjected to SDS-PAGE, followed by fluorography of the dried gel.

Tideglusib is an irreversible, non ATP-competitive GSK-3β inhibitor with IC50 of 60 nM in a cell-free assay; fails to inhibit kinases with a Cys homologous to Cys-199 located in the active site. Phase 2.