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    Tideglusib (NP-031112, NP-12)
    Tideglusib (NP-031112, NP-12)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0215
    CAS #: 865854-05-3Purity ≥98%

    Description: Tideglusib (formerly known as NP031112, NP12) is a novel, potent, irreversible, non-ATP-competitive and chemical inhibitor of GSK-3β (glycogen synthase kinase-3β) with potential neuroprotective effects and may be used as an anti-AD (Alzheimer disease) agent. It inhibits GSK-3β with an IC50 of 60 nM in cell-free assay; Tideglusib is currently undergoing phase II clinical trials for Alzheimer disease and progressive supranuclear palsy. Tideglusib inhibits GSK-3β irreversibly, as shown by the lack of recovery in enzyme function after the unbound Tideglusib was removed from the reaction medium; Also, its dissociation rate constant is non-significantly different from zero. In addition, tideglusib failed to inhibit a variety of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. 

    References:  J Biol Chem. 2012 Jan 6;287(2):893-904; J Neurosci. 2007 May 23;27(21):5766-76.

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    Molecular Weight (MW)

    334.39

    Formula

    C19H14N2O2S

    CAS No.

    865854-05-3

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 66 mg/mL (197.4 mM)          

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    Solubility (In vivo)

    4% DMSO+corn oil: 2.5 mg/mL

    Synonyms

    Tideglusib; NP031112, NP-12; NP031112; NP 031112; NP-031112

    Chemical Name: 2-(1-naphthalenyl)-4-(phenylmethyl)-1,2,4-thiadiazolidine-3,5-dione

    InChi Key: PMJIHLSCWIDGMD-UHFFFAOYSA-N

    InChi Code: InChI=1S/C19H14N2O2S/c22-18-20(13-14-7-2-1-3-8-14)19(23)24-21(18)17-12-6-10-15-9-4-5-11-16(15)17/h1-12H,13H2

    SMILES Code: O=C(N1CC2=CC=CC=C2)N(C3=C4C=CC=CC4=CC=C3)SC1=O


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    In Vitro

    In vitro activity: Tideglusib irreversibly inhibits GSK-3, reduces tau phosphorylation, and prevents apoptotic death in human neuroblastoma cells and murineprimary neurons. Tideglusib (2.5 μM) inhibits glutamate-induced glial activation as evidenced by decreased TNF-α and COX-2 expression in rat primary astrocyte or microglial cultures. Tideglusib (2.5 μM) 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.

     

    Kinase Assay: [35S]Tideglusib (207 Bq/nmol) at 55 μM is incubated with 5 μM GSK-3β for 1 h at 25°C in 315 μL 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 μL of the same buffer with or without 100 mM DTE. Samples are then processed in three different ways. First, an aliquot of 125 μL of each sample is mixed with 375 μL of 8 M GdnHCl in H2O and heated at 80°C for 5 min. A second aliquot of 125 μL is diluted up to 500 μL with H2O and left at room temperature for 5 min. In both cases, the free drug is removed afterwards by gel filtration through Sephadex G-25, and the amount of bound drug is determined by liquid scintillation counting on a 1450-MicroBeta TriLux counter. Finally, a third 40 μL aliquot of each original sample is mixed with 10 μL of denaturing electrophoresis sample buffer without reducing agents, and 35 μL of this mixture is loaded onto a 10% polyacrylamide gel and subjected to SDS-PAGE (again in the absence of reducing agents except for the DTE already included in the corresponding sample), followed by fluorography of the dried gel. 

     

    Cell Assay: Tideglusib (NP12) is a small heterocyclic thiadiazolidinone (TDZD) derivative, which is an ATP-non competitive inhibitor of GSK-3β with an IC50value in the micromolar range. Incubation of both astrocyte and microglial cultures with Tideglusib (NP031112) completely abrogates the induction of TNF-α and COX-2 expression after glutamate treatment. These effects of NP031112 are not caused by a loss of cell viability, because the 24 h exposure of astrocyte and microglial cells to this TDZD does not modify cell viability.

    In Vivo

    Tideglusib (50 mg/kg) injected into the adult male Wistar rats hippocampus dramatically reduces kainic acid-induced inflammation and has a neuroprotective effect in the damaged areas of the hippocampus. Tideglusib (200 mg/kg, oral) results in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in APP/tau double transgenic mice.

    Animal model

    Transgenic APPsw-tauvlw mice overexpressing human mutant APP and a triple human tau mutation.

    Formulation & Dosage

    Formulated in 26% peg400 (Polyethylene Glycol 400), 15% Chremophor EL and water; 200 mg/kg; Oral gavage

    References

    J Biol Chem. 2012 Jan 6;287(2):893-904; J Neurosci. 2007 May 23;27(21):5766-76.  


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    • Lot#: V021502,Purity ≥98%

    • COA

    Tideglusib

    Double reciprocal plots of the inhibition caused by tideglusib on GSK-3β. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Activity of samples from the filtration-dilution process. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Tideglusib and other TDZDs as time-dependent inhibitors.. 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Time course of tideglusib inhibition on GSK-3β. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Inhibition caused by hypothemycin and tideglusib on a panel of selected human recombinant kinases. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Time course of tideglusib inhibition on GSK-3β C199A. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Binding experiments with [35S]tideglusib. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Half-life of GSK-3β in mouse cortical neurons. . 2012 Jan 6; 287(2): 893–904.

    Tideglusib

    Correlation between K1 and k3/K1 values reported in Ref. . 2012 Jan 6; 287(2): 893–904.


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