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Tideglusib

Tideglusib structure

CAS No:
865854-05-3
Formula:
C19H14N2O2S
Chemical Name:
Tideglusib
Synonyms:
1,2,4-Thiadiazolidine-3,5-dione,2-(1-naphthalenyl)-4-(phenylmethyl)-;2-(1-Naphthalenyl)-4-(phenylmethyl)-1,2,4-thiadiazolidine-3,5-dione;4-Benzyl-2-(naphthalen-1-yl)-[1,2,4]thiadiazolidine-3,5-dione;Tideglusib;NP 12;NP 031112;945421-01-2;1073650-08-4
Categories:
Biochemical Engineering > Inhibitors

Description

Tideglusib is an irreversible GSK-3 inhibitor with IC50s of 5 nM and 60 nM for GSK-3βWT (1 h preincubation) and GSK-3βC199A (1 h preincubation), respectively.

Tideglusib is a member of the class of thiadiazolidines that is 1,2,4-thiadiazolidine-3,5-dione which is substituted by a naphthalen-1-yl group at position 2 and by a benzyl group at position 4. It is a non-ATP competitive inhibitor of glycogen synthase kinase 3beta (GSK3beta) and has neuroprotective effects. Currently under clinical investigation for the treatment of Alzheimer's disease and progressive supranuclear palsy. It has a role as an EC 2.7.11.26 (tau-protein kinase) inhibitor, a neuroprotective agent, an anti-inflammatory agent and an apoptosis inducer. It is a member of naphthalenes, a member of benzenes and a thiadiazolidine.|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). Tideglusib is being developed by the Spanish pharmaceutic company Zeltia group and its current status is withdrawn for the treatment of Alzheimer's disease as of 2012.

Tideglusib Basic Attributes

Molecular Weight：

334.39166

Exact Mass：

334.39

UNII：

Q747Y6TT42

DSSTox ID：

DTXSID90235682

Characteristics

PSA：

65.9

XLogP3：

4.3

Appearance：

white to beige

Density：

1.4±0.1 g/cm3

Melting Point：

148-150ºC

Boiling Point：

511.3ºC at 760 mmHg

Flash Point：

263.0±28.2 °C

Refractive Index：

1.735

Water Solubility：

Sparingly soluble with water.DMSO: >15mg/mL

Storage Conditions：

2-8°C

Safety Information

Transport codes：

NONH for all modes of transport

wgk germany：

Toxicity

Toxicity Summary：

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

Drug Information

Drug Indication：

Tideglusib was initially formulated for the treatment of Alzheimer and progressive supranuclear palsy. 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. 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. 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.

Pharmacology：

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. 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.

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. 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.

MeSH Entry Terms：

4-benzyl-2-(naphthalene-1-yl)-1,2,4-thiadiazolidine-3,5-dione

Tideglusib Use and Manufacturing

Use Classification：

Human drugs -> Rare disease (orphan)

Computed Properties

Molecular Weight:334.4
XLogP3:4.3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:334.07759887
Monoisotopic Mass:334.07759887
Topological Polar Surface Area:65.9
Heavy Atom Count:24
Complexity:492
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

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