VX-765Caspase-1 inhibitor,potent and selective CAS# 273404-37-8 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 273404-37-8 | SDF | Download SDF |
PubChem ID | 11398092 | Appearance | Powder |
Formula | C24H33ClN4O6 | M.Wt | 508.99 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | Belnacasan | ||
Solubility | DMSO : 50 mg/mL (98.23 mM; Need ultrasonic) H2O : 1 mg/mL (1.96 mM; ultrasonic and warming and heat to 60°C) | ||
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 | ||
SMILES | CCOC1C(CC(=O)O1)NC(=O)C2CCCN2C(=O)C(C(C)(C)C)NC(=O)C3=CC(=C(C=C3)N)Cl | ||
Standard InChIKey | SJDDOCKBXFJEJB-MOKWFATOSA-N | ||
Standard InChI | InChI=1S/C24H33ClN4O6/c1-5-34-23-16(12-18(30)35-23)27-21(32)17-7-6-10-29(17)22(33)19(24(2,3)4)28-20(31)13-8-9-15(26)14(25)11-13/h8-9,11,16-17,19,23H,5-7,10,12,26H2,1-4H3,(H,27,32)(H,28,31)/t16-,17-,19+,23+/m0/s1 | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | VX-765 is a novel Caspase-1 inhibitor being investigated for the treatment of epilepsy, currently being developed by Vertex. | |||||
Targets | Caspase-1 |
VX-765 Dilution Calculator
VX-765 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 1.9647 mL | 9.8234 mL | 19.6468 mL | 39.2935 mL | 49.1169 mL |
5 mM | 0.3929 mL | 1.9647 mL | 3.9294 mL | 7.8587 mL | 9.8234 mL |
10 mM | 0.1965 mL | 0.9823 mL | 1.9647 mL | 3.9294 mL | 4.9117 mL |
50 mM | 0.0393 mL | 0.1965 mL | 0.3929 mL | 0.7859 mL | 0.9823 mL |
100 mM | 0.0196 mL | 0.0982 mL | 0.1965 mL | 0.3929 mL | 0.4912 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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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].
References:
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.
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(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.[Pubmed:17289835]
J Pharmacol Exp Ther. 2007 May;321(2):509-16.
(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) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimeth yl-butanoyl)-pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of interleukin (IL)-1beta and IL-18, but it had little effect on the release of several other cytokines, including IL-1alpha, tumor necrosis factor-alpha, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis, and it did not affect the proliferation of activated primary T cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice, and it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.
Development of a novel Pd-catalyzed N-acyl vinylogous carbamate synthesis for the key intermediate of ICE inhibitor VX-765.[Pubmed:18081302]
Org Lett. 2008 Jan 17;10(2):185-8.
A novel Pd-catalyzed coupling of Cbz-protected proline amide with 4-bromo-5-ethoxyfuran-2(5H)-one was developed for the synthesis of the P1-P2 unit (5) of VX-765. The process afforded quantitative coupling in the presence of water, providing a 1:1 mixture of 5 and its ethoxy epimer epi-5. Compound 5 was isolated as a single diastereomer via fractional crystallization, which was stereoselectively converted to 17 via hydrogenation, and subsequently transformed to VX-765. Nine examples of the Pd coupling are presented with yields ranging from 76-98%.
IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.[Pubmed:16081838]
J Immunol. 2005 Aug 15;175(4):2630-4.
Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.