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VX-765Caspase-1 inhibitor,potent and selective

VX-765

Catalog No. A8238
Size Price Stock Qty
10mM (in 1mL DMSO) $85.00 In stock
5mg $70.00 In stock
10mg $100.00 In stock
50mg $250.00 In stock
100mg $450.00 In stock

Tel: +1-832-696-8203

Email: sales@apexbt.com

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Sample solution is provided at 25 µL, 10mM.

Product Citations

1. Zaccara, Gaetano, and Dieter Schmidt. "Do traditional anti-seizure drugs have a future? A review of potential anti-seizure drugs in clinical development." Pharmacological research 104 (2016): 38-48. PMID:26689774

Quality Control

Quality Control & MSDS

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Chemical structure

VX-765

Biological Activity

VX-765 is a novel Caspase-1 inhibitor being investigated for the treatment of epilepsy, currently being developed by Vertex.
Targets Caspase-1          
IC50            

Protocol

Kinase experiment [1]:

Protease enzyme assays

Enzyme inhibition was assayed by tracking of the rate of hydrolysis of an appropriate substrate labeled with either p-nitroaniline or aminomethyl coumarin (AMC) as follows: ICE/caspase-1, suc-YVAD-p-nitroanilide; caspase-4, Ac-WEHD-AMC; caspase-6, Ac-VEID-AMC; caspase-3, -7, -8, and -9, Ac-DEVD-AMC; and granzyme B, Ac-IEPD-AMC. Enzymes and substrates were incubated in a reaction buffer [10 mM Tris, pH 7.5, 0.1% (w/v) CHAPS, 1 mM dithiothreitol, and 5% (v/v) dimethyl sulfoxide] for 10 mins at 37 °C. Glycerol was added to the buffer at 8% (v/v) for caspase-3, -6, and -9 and granzyme B to improve stability of enzymes. The rate of substrate hydrolysis was monitored using a fluorometer.

Animal experiment [1]:

Animal models

Collagen-induced arthritis (CIA) mouse model

Dosage form

10, 25, 50 or 100 mg/kg; p.o.; b.i.d.; for 24 days.

Applications

In a CIA mouse model, VX-765 significantly reduced the inflammation scores in a dose-dependent manner. In addition, 100 mg/kg VX-765 was as efficacious as 5 mg/kg Prednisolone.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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.

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Chemical Properties

Cas No. 273404-37-8 SDF Download SDF
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
Canonical SMILES CCOC1C(CC(=O)O1)NC(=O)C2CCCN2C(=O)C(C(C)(C)C)NC(=O)C3=CC(=C(C=C3)N)Cl
Formula C24H33ClN4O6 M.Wt 508.99
Solubility >25.5mg/mL in DMSO Storage Desiccate at -20°C
General tips N/A
Shipping Condition N/A

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.