Explore a selection of our essential drug information below, or:
Identification
- Generic Name
- Tideglusib
- DrugBank Accession Number
- DB12129
- Background
Tideglusib is under the investigation for the development of treatments for Alzheimer's disease and for progressive supranuclear palsy. It is reported to be a potent anti-inflammatory and neuroprotective that is a non-ATP competitive inhibitor of glycogen synthase kinase 3 (GSK-3).1 Tideglusib is being developed by the Spanish pharmaceutic company Zeltia group and its current status is withdrawn for the treatment of Alzheimer's disease as of 2012.
- Type
- Small Molecule
- Groups
- Investigational, Withdrawn
- Structure
Structure for Tideglusib (DB12129)
- Weight
- Average: 334.39
Monoisotopic: 334.077598873 - Chemical Formula
- C19H14N2O2S
- Synonyms
- 4-BENZYL-2-(A-NAPHTYL)-1,2,4-THIADIAZOLIDINE-3,5-DIONE
- 4-Benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione
- Tideglusib
- External IDs
- NP-031112
- NP-12
- NP031112
Pharmacology
- Indication
Tideglusib was initially formulated for the treatment of Alzheimer and progressive supranuclear palsy.1 The raising interest for the use of tideglusib comes from the significant upregulation of GSK-3 in the brain in patients with Alzheimer disease. Its function as a degradant of β-catenin, was also important, as it prevents the transcription of cell survival genes. All these factors have directed current research towards this kinase as a potential target.3 Alzheimer disease is the most prevalent form of dementia. The most accepted hypothesis to explain this disease is related to the presence of amyloid β, which triggers a cascade that will alter the Tau protein and provoke synaptic dysfunction and neuronal death.4
GSK-3 importance in the tissue repair pathway has also pointed out a novel application for tideglusib. Thus, it is also under the research for the natural repair treatment of deep caries lesions.2
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It is reported that tideglusib administration inhibits the activation of astrocytes and microglial cells, thus it presented a neuroprotective effect. It is known as well that the inactivation of GSK-3 protects against excitotoxicity.1 In pre-clinical trials, there have been reports of decrease Tau hyperphosphorylation, lower brain amyloid plaque load, learning and memory enhancement, prevention of neuronal loss and significant increases of the insulin growth factor 1 which is a potent neurotrophic peptide with therapeutic value.The reports in clinical trials have shown a trend in cognition increase of Alzheimer patients treated for 24 weeks.3,4
- Mechanism of action
GSK-3 is a proline/serine protein kinase that is ubiquitously expressed and involved in many cellular signaling pathways. From all its diverse functions, it plays a key role in Alzheimer's disease. This role is related to its link with β-amyloid and tau pathology. It has been suggested that aberrant Wnt or insulin signaling results in increased GSK-3 function. This kinase acts on γ-secretase producing the hyperphosphorylation of tau, the formation of neurofibrillary tangles and senile plaques.3 Tideglusib inhibits GSK-3 irreversibly by presenting a non-competitive inhibition pattern with respect to ATP. The binding of tideglusib seems to directly relate to the motif containing Cys199.4
Target Actions Organism AGlycogen synthase kinase-3 beta antagonistHumans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
In preclinical studies, tideglusib showed no significant toxicity reported as weight loss or activity changes.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as naphthalenes. These are compounds containing a naphthalene moiety, which consists of two fused benzene rings.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Naphthalenes
- Sub Class
- Not Available
- Direct Parent
- Naphthalenes
- Alternative Parents
- Benzene and substituted derivatives / Thiadiazoles / Heteroaromatic compounds / Azacyclic compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
- Substituents
- Aromatic heteropolycyclic compound / Azacycle / Azole / Heteroaromatic compound / Hydrocarbon derivative / Monocyclic benzene moiety / Naphthalene / Organic nitrogen compound / Organic oxide / Organic oxygen compound
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- Q747Y6TT42
- CAS number
- 865854-05-3
- InChI Key
- PMJIHLSCWIDGMD-UHFFFAOYSA-N
- InChI
- 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
- IUPAC Name
- 4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione
- SMILES
- O=C1SN(C(=O)N1CC1=CC=CC=C1)C1=C2C=CC=CC2=CC=C1
References
- General References
- Luna-Medina R, Cortes-Canteli M, Sanchez-Galiano S, Morales-Garcia JA, Martinez A, Santos A, Perez-Castillo A: NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J Neurosci. 2007 May 23;27(21):5766-76. doi: 10.1523/JNEUROSCI.1004-07.2007. [Article]
- Neves VC, Babb R, Chandrasekaran D, Sharpe PT: Promotion of natural tooth repair by small molecule GSK3 antagonists. Sci Rep. 2017 Jan 9;7:39654. doi: 10.1038/srep39654. [Article]
- Martinez A, Gil C, Perez DI: Glycogen synthase kinase 3 inhibitors in the next horizon for Alzheimer's disease treatment. Int J Alzheimers Dis. 2011;2011:280502. doi: 10.4061/2011/280502. Epub 2011 Jun 30. [Article]
- Dominguez JM, Fuertes A, Orozco L, del Monte-Millan M, Delgado E, Medina M: Evidence for irreversible inhibition of glycogen synthase kinase-3beta by tideglusib. J Biol Chem. 2012 Jan 6;287(2):893-904. doi: 10.1074/jbc.M111.306472. Epub 2011 Nov 18. [Article]
- Bharathy N, Svalina MN, Settelmeyer TP, Cleary MM, Berlow NE, Airhart SD, Xiang S, Keck J, Hayden JB, Shern JF, Mansoor A, Lathara M, Srinivasa G, Langenau DM, Keller C: Preclinical testing of the glycogen synthase kinase-3beta inhibitor tideglusib for rhabdomyosarcoma. Oncotarget. 2017 Jun 16;8(38):62976-62983. doi: 10.18632/oncotarget.18520. eCollection 2017 Sep 8. [Article]
- External Links
- PubChem Compound
- 11313622
- PubChem Substance
- 347828428
- ChemSpider
- 9488589
- BindingDB
- 50166940
- ChEBI
- 147398
- ChEMBL
- CHEMBL3545157
- ZINC
- ZINC000013985228
- Wikipedia
- Tideglusib
- MSDS
- Download (22.2 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data2 Completed Treatment Alzheimer's Disease (AD) 1 somestatus stop reason just information to hide 2 Completed Treatment Autism Disorder 1 somestatus stop reason just information to hide 2 Completed Treatment Steinert's Disease 1 somestatus stop reason just information to hide 2 Not Yet Recruiting Treatment Amyotrophic Lateral Sclerosis (ALS) 1 somestatus stop reason just information to hide 2 Not Yet Recruiting Treatment Arrhythmogenic Cardiomyopathies / Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 148-150ºC 'MSDS' boiling point (°C) 511.3ºC at 760 mmHg 'MSDS' water solubility Sparingly soluble Product information sheet. logP 3.28 'MSDS' - Predicted Properties
Property Value Source Water Solubility 0.00704 mg/mL ALOGPS logP 3.44 ALOGPS logP 4.72 Chemaxon logS -4.7 ALOGPS Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 40.62 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 94.91 m3·mol-1 Chemaxon Polarizability 34.22 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-006x-9553000000-ae8ccbc73d116bfc501b Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-2009000000-dbfd210c7944f4982ca7 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-22b8fb8cc8ed2abd88d0 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0219000000-7afab1ba9a173d341c10 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-2009000000-6b130d06868413c52862 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0uk9-0900000000-d6d32cfe61b6b17b2337 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-05fr-2901000000-15b59f0a3648a1c26497 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 187.1956325 predictedDarkChem Lite v0.1.0 [M-H]- 172.30878 predictedDeepCCS 1.0 (2019) [M+H]+ 174.6668 predictedDeepCCS 1.0 (2019) [M+Na]+ 181.42192 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:11430833, PubMed:12554650, PubMed:14690523, PubMed:16484495, PubMed:1846781, PubMed:20937854, PubMed:9072970). Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281). Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282, PubMed:25827072, PubMed:29059170). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation (By similarity). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome (By similarity). Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its proteasomal degradation (By similarity)
- Specific Function
- Atp binding
- Gene Name
- GSK3B
- Uniprot ID
- P49841
- Uniprot Name
- Glycogen synthase kinase-3 beta
- Molecular Weight
- 46743.865 Da
References
- Martinez A, Gil C, Perez DI: Glycogen synthase kinase 3 inhibitors in the next horizon for Alzheimer's disease treatment. Int J Alzheimers Dis. 2011;2011:280502. doi: 10.4061/2011/280502. Epub 2011 Jun 30. [Article]
Drug created at October 20, 2016 21:24 / Updated at July 18, 2023 22:56