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Tideglusib

现货
Catalog No.
B1539
非ATP竞争性GSK-3β抑制剂
组合的产品项目
规格价格库存 数量
10mg
¥ 800.00
现货
50mg
¥ 1,200.00
现货
200mg
¥ 3,300.00
现货

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Background

IC50: A potent, selective and irreversible non-ATP-competitive GSK-3β suppressor with an IC50 of 60 nM.

Tideglusib is a GSK-3 inhibitor currently undergoing phase II clinical trials for Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of Tideglusib to animal models could down-regulates Tau hyper-phosphorylation, reduces brain amyloid plaque load, promotes learning and memory as well as prevents neuronal loss. [1]

In vitro: In vitro studies showed that after the unbound Tideglusib was removed from the reaction medium, the enzyme function could not be recovered. In addition, the dissociation rate constant of the reaction was as low as nearly zero. All above findings suggested that Tideglusib blocked GSK-3 irreversibly. Such irreversibility might be responsible for the non-competitive inhibition pattern with respect to ATP of Tideglusib and perhaps other structurally related compounds. [1]

In vivo: Based on double transgenic mice model co-expressing human mutant APP and tau, a study demonstrated that Tideglusib could suppress GSK-3, reduced amyloid and tau pathologies, blocked neuronal cell death and memory deficits in vivo. [2]

Clinical trial: A pilot, double-blind, placebo-controlled and randomized clinical trial was conducted to study the effect of Tideglusib in AD patients with an escalating dose. Thirty patients with mild to moderate AD were orally administered with Tideglusib in escalating doses of 400, 600, 800 and 1000 mg for periods of 4, 4, 6 and 6 weeks, respectively. This pilot study proved the safety and effectiveness of Tideglusib in AD patients. [3]

References:
[1]Domínguez JM, Fuertes A, Orozco L, Monte-Millan MD, Delgado E and Medina M.  Evidence for irreversible inhibition of glycogen synthase kinase-3 by Tideglusib. J Biol Chem. 2012 Jan; 287(2): 893-904.
[2]Serenóa L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T.  A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009 Sep; 35(3): 359-67.
[3]del Ser, T.  Phase IIA clinical trial on Alzheimer’s Disease with NP-12, a GSK-3 inhibitor. Alzheimers and Dement. 2010; 6: S147.

文献引用

1. Croft CL, Cruz PE, et al. "rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies." J Exp Med. 2019 Mar 4;216(3):539-555. PMID:30770411

Chemical Properties

StorageStore at -20°C
M.Wt334.39
Cas No.865854-05-3
FormulaC19H14N2O2S
Solubility≥16.7 mg/mL in DMSO with gentle warming, <1.67 mg/mL in EtOH, <1.71 mg/mL in H2O
Chemical Name4-benzyl-2-naphthalen-1-yl-1,2,4-thiadiazolidine-3,5-dione
SDFDownload SDF
Canonical SMILESC1=CC=C(C=C1)CN2C(=O)N(SC2=O)C3=CC=CC4=CC=CC=C43
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验[1]:

细胞系

草地贪夜蛾Sf21细胞(表达N端带有His6-tag的人源重组GSK-3β)

溶解方法

在DMSO中的溶解度>15 mg/mL。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

55μM,1h,25°C .

应用

在表达人类重组GSK-3β的Sf21细胞中,Tideglusib 不可逆的阻断了GSK-3β。在兴奋性毒性条件下,Tideglusib可以阻止炎症反应和神经退行性病变。

动物实验 [2]:

动物模型

转基因APPsw-tauvlw C57Bl6j/SJL/CBA混合杂交遗传小鼠【过表达人源突变APP和带有三个突变的人源tau(17号染色体的G272V, P301L, R406W突变)】

剂量

溶解于26% peg400(聚乙二醇400),15% Chremophor EL和水的混合溶液中;200 mg/kg每天;持续几个月;口服。

应用

在该转基因小鼠模型中,使用Tideglusib可以抑制tau磷酸化,降低淀粉样沉积物,抑制老年斑相关的星形细胞增殖,防止内嗅皮层和海马CA1区神经元死亡,预防记忆障碍。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Domínguez JM, Fuertes A, et al, Evidence for irreversible inhibition of glycogen synthase kinase-3 by Tideglusib. J Biol Chem. 2012 Jan; 287(2): 893-904.

[2] Luna-Medina R1, Cortes-Canteli M, et al, 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.

[3] Serenóa L, Coma M, et al, A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009 Sep; 35(3): 359-67.

质量控制

化学结构

Tideglusib

相关生物数据

Tideglusib