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VX-765

现货
Catalog No.
A8238
有效的Caspase-1选择性抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 850.00
现货
5mg
¥ 700.00
现货
10mg
¥ 1,000.00
现货
50mg
¥ 2,500.00
现货
100mg
¥ 4,500.00
现货

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Background

VX-765, an orally- absorbed pro-drug of VRT-043198, is a potent and selective inhibitor of caspase-1 which belongs to the ICE/caspase-1 sub-family caspases.

Caspase-1, known as interleukin (IL)-1-converting enzyme, is responsible for the processing of a key inflammatory mediator IL-1β from an in active precursor to an active, secreted protein. In response to intracellular bacteria, caspase-1 is also reported to be involved in a rapid programme of cell death, termed pyroptosis in macrophages [1].

VX-765 is usually metabolized to an active molecular VRT-043198. In cultures of peripheral blood mononuclear cells stimulated with bacterial products, VRT-043198 inhibited the release of Interleukin (IL)-1β and IL-18, but had no affect the secretion of other cytokines such as IL-α, TNFα, IL-6 and IL-8 [2].

This product is also used in other models to illustrate the function of Caspase-1. Oral administration of VX-765 significantly reduced the severity of diseases and the inflammatory cytokines and chemokines secretion in the mouse model of rheumatoid arthritis and skin inflammation[1]. In addition, recent study demonstrated that VX-765 prevents CD4 T-cell pyroptotic death in a dose-dependent manner in HIV-infected lymphoid tissues [3].

Reference:
1. Denes A, Lopez-Castejon G, Brough D. Caspase-1: is IL-1 just the tip of the ICEberg Cell Death Dis 2012,3:e338.
2. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 2007,321:509-516.
3. Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 2014,505:509-514.

文献引用

1. Yang G, Wang J, et al. "White spot syndrome virus infection activates Caspase 1-mediated cell death in crustacean." Virology. 2018 Dec 13;528:37-47. PMID:30554072

Chemical Properties

Physical AppearanceA solid
StorageDesiccate at -20°C
M.Wt508.99
Cas No.273404-37-8
FormulaC24H33ClN4O6
Solubility≥313 mg/mL in DMSO, ≥50.5 mg/mL in EtOH with ultrasonic, <2.71 mg/mL in H2O
Chemical Name(2S)-1-[(2S)-2-[(4-amino-3-chlorobenzoyl)amino]-3,3-dimethylbutanoyl]-N-[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]pyrrolidine-2-carboxamide
SDFDownload SDF
Canonical SMILESCCOC1C(CC(=O)O1)NC(=O)C2CCCN2C(=O)C(C(C)(C)C)NC(=O)C3=CC(=C(C=C3)N)Cl
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

激酶实验 [1]:

蛋白酶试验

通过测定底物水解速率评估酶抑制程度。使用对硝基苯胺或氨甲基香豆素 (AMC) 标记的底物,如:ICE/caspase-1,suc-YVAD-对硝基苯胺;caspase-4,Ac-WEHD-AMC;caspase-6,Ac-VEID-AMC;caspase-3,caspase-7,caspase-8,和caspase-9,Ac-DEVD-AMC;颗粒酶B,Ac-IEPD-AMC。将酶和底物加入到反应缓冲液中 [10 mM Tris,pH 7.5,0.1% (w/v) CHAPS,1 mM 二硫苏糖醇以及5% (v/v) 二甲基亚砜],置于37 °C下孵育10分钟。将甘油8% (v/v)加入caspase-3、caspase-6、caspase-9 和颗粒酶B的缓冲液中,以提高酶的稳定性。使用荧光计测定底物水解速率。

动物实验 [1]:

动物模型

胶原诱导性关节炎 (CIA) 小鼠模型

给药剂量

10、25、50或100 mg/kg;口服给药;每日2次,持续24天

实验结果

在CIA小鼠模型中,VX-765显著地呈剂量依赖性地减少炎症分数。此外,100 mg/kg VX-765与5 mg/kg Prednisolone具有相同的效果。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 2007,321:509-516.

生物活性

VX-765是一种新型的Caspase-1抑制剂,被研究用于癫痫的治疗,目前正由Vertex开发。
靶点 Caspase-1          
IC50            

质量控制

化学结构

VX-765

相关生物数据

VX-765