Tideglusib

Identification

Name
Tideglusib
Accession Number
DB12129
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

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3 (GSK-3).[1] Tideglusib is being developed by the Spanish pharmaceutic company Zeltia group and its current status is withdrawn for the treatment of Alzheimer's disease as of 2012.

Structure
Thumb
Synonyms
Not Available
External IDs
NP-031112 / NP-12 / NP031112
Categories
UNII
Q747Y6TT42
CAS number
865854-05-3
Weight
Average: 334.39
Monoisotopic: 334.077598873
Chemical Formula
C19H14N2O2S
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

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]

Pharmacodynamics

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]

TargetActionsOrganism
AGlycogen synthase kinase-3 beta
antagonist
Humans
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
Toxicity

In preclinical studies, tideglusib showed no significant toxicity reported as weight loss or activity changes.[5]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:17522320]
  2. 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. [PubMed:28067250]
  3. 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. [PubMed:21760986]
  4. 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. [PubMed:22102280]
  5. 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. [PubMed:28968964]
External Links
PubChem Compound
11313622
PubChem Substance
347828428
ChemSpider
9488589
BindingDB
50166940
ChEMBL
CHEMBL3545157
Wikipedia
Tideglusib
MSDS
Download (22.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentAlzheimer's Disease (AD)1
2CompletedTreatmentAlzheimer's Disease (AD)1
2CompletedTreatmentAutism Spectrum Conditions/Disorders1
2CompletedTreatmentMyotonic Dystrophy 11
2, 3Not Yet RecruitingTreatmentCongenital Myotonic Dystrophy1
Not AvailableCompletedTreatmentProgressive Supranuclear Palsy (PSP)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)148-150ºC'MSDS'
boiling point (°C)511.3ºC at 760 mmHg'MSDS'
water solubilitySparingly solubleProduct information sheet.
logP3.28'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.00704 mg/mLALOGPS
logP3.44ALOGPS
logP4.72ChemAxon
logS-4.7ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area40.62 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity94.91 m3·mol-1ChemAxon
Polarizability34.22 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Naphthalene / Monocyclic benzene moiety / Heteroaromatic compound / Thiadiazole / Azole / Azacycle / Organoheterocyclic compound / Organic nitrogen compound / Organic oxygen compound / Organic oxide
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Ubiquitin protein ligase binding
Specific 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 pho...
Gene Name
GSK3B
Uniprot ID
P49841
Uniprot Name
Glycogen synthase kinase-3 beta
Molecular Weight
46743.865 Da
References
  1. 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. [PubMed:21760986]

Drug created on October 20, 2016 15:24 / Updated on November 02, 2018 07:20