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VX-765

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Chemical Structure| 273404-37-8 同义名 : Belnacasan
CAS号 : 273404-37-8
货号 : A100567
分子式 : C24H33ClN4O6
纯度 : 99%+
分子量 : 508.995
MDL号 : MFCD23102811
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(206.29 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO

H2O: 1 mg/mL(1.96 mM)，配合低频超声，并水浴加热至45℃助溶
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 10 mg/mL clear

PO 0.5% CMC-Na 28 mg/mL suspension

生物活性
靶点

  • Caspase-4

    Caspase-4, Ki:<0.6 nM

  • Caspase-1

    Caspase-1, Ki:0.8 nM
描述 Caspase-1, also called as interleukin-converting enzyme (ICE), is the cysteine protease able to cleave pro-IL-1 and pro-IL-18 to the active cytokines IL-1 and IL-18, both of which are important to the acute and chronic stages of inflammatory immune responses. VX-765 is the prodrug of VRT-043198, which is a selective inhibitor of caspase-1 subfamily caspases with Ki value of 0.8nM for caspase-1 and <0.6nM for caspase-4 (measured by protease enzyme assays), respectively, and exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. As its inactivation against caspase-1, VRT-043198 inhibited LPS-stimulated release of cytokines, IL-1,from both PBMCs and whole blood with IC50 values of 0.67μM and 1.9μM, respectively. Also, VRT-043198 could dose-dependently inhibit SAC(S. aureusCowan strain 1)-stimulated release of IL-1, IL-18 and IFN-γ with IC50 values of 0.87μM, 2.8μM and 5.6μM, respectively, from human PBMCs, but not TNF-α. It was found that VRT-043198 lacked potent anti-apoptotic activity as its low potency against caspase-9, but effective on Fas-induced apoptosis in the Jurkat human T-cell line, where initiation of the apoptosis cascade is mediated by caspase-8 activity. When orally dosed mice with VX-765, it can be efficiently converted to VRT-043198. A single dose of VX-765 at dose of 50-200mg/kg 1h before LPS injection reduced serum IL-1 levels up to 60% after 2.5h in peripheral blood samples from LPS-injected mice. Oral administration of VX-765 at dose of 25, 50 and 100 mg/kg, at 24 and 36 h after challenge by oxazolone, caused reduced production of inflammatory mediators in biopsy samples from oxazolone-challenged mouse ears, including IL-1, IL-18, IFN-γ, nitric oxide and MIP-2 (at all dose), MCP-1 and MIP-1α(50 and mg/kg), IL-4 and myeloperoxidase (100mg/kg). VX-765 at dose of 10, 25, 50, or 100 mg/kg, b.i.d., for 24 days, could significantly reduce the forepaw inflammation in the mouse CIA model, as well as reduced disease severity in models of collagen-induced-rheumatoid arthritis, suggesting that suggest that VX-765 may be a novel cytokine inhibitor and useful for treatment of inflammatory diseases[1]. VX-765 prevented pyroptosis by prevention of GSDMD cleavage, a cleavage target of caspase-1 and caspase-11. The differential ability of VX-765 and Ac-YVAD-cmk to inhibit pyroptosis was reflected in the prevention of GSDMD cleavage by VX-765, but not by Ac-YVAD-cmk[5].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.96mL

0.39mL

0.20mL

9.82mL

1.96mL

0.98mL

19.65mL

3.93mL

1.96mL
参考文献

[1]Wannamaker W, Davies R, et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl] -amino}-3,3-dimethyl-butanoyl)-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 May;321(2):509-16. Epub 2007 Feb 8.

[2]Ravizza T, Lucas SM, et al. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia. 2006;47(7):1160-8.

[3]Yang XM, Downey JM, et al. The Highly Selective Caspase-1 Inhibitor VX-765 Provides Additive Protection Against Myocardial Infarction in Rat Hearts When Combined With a Platelet Inhibitor. J Cardiovasc Pharmacol Ther. 2017;22(6):574-578.

[4]Maroso M, Balosso S, et al. Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 2011;8(2):304-15.

[5]Schneider KS, Groß CJ, Dreier RF, et al. The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity. Cell Rep. 2017;21(13):3846-3859

[6]García-Fernández A, García-Laínez G, et al. Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles. J Control Release. 2017 Feb 28;248:60-70.