生物活性

• 靶点	Caspase 1 Ki:0.8nM

• 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].

• 动物研究
  剂量	Rat: 50 mg/kg - 200 mg/kg[2] (i.p.) Mice: 10 mg/kg - 84 mg/kg[1] (p.o.), 4.2 mg/kg - 10 mg/kg[6] (i.v.)
  给药途径	i.p., p.o., i.v.
  动物药代数据	Animal Mice[1] Dose 84 mg/kg Administration p.o. Cmax 0.78 μg/ml T1/2 1.0 h AUClast 2.06 μg·h/ml

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00205465	Psoriasis	Phase 2	Completed	-	-
  NCT01501383	Epilepsy	Phase 2	Terminated(Terminated by Spons... more >>or) Collapse <<	-	-
  NCT01048255	Partial Epilepsy	Phase 2	Completed	-	United States, Arkansas ... more >> Arkansas Little Rock, Arkansas, United States United States, California California Newport Beach, California, United States United States, Florida Florida Miami, Florida, United States Florida Sarasota, Florida, United States United States, Illinois Illinois Chicago, Illinois, United States United States, Maryland Maryland Baltimore, Maryland, United States Maryland Bethesda, Maryland, United States United States, Missouri Missouri Chesterfield, Missouri, United States United States, New Jersey New Jersey Hackensack, New Jersey, United States United States, New York New York New York, New York, United States United States, Pennsylvania Pennsylvania Philidelphia, Pennsylvania, United States United States, Virginia Virginia Charlottesville, Virginia, United States Collapse <<

• 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.

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