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531372 Caspase-1/4 Inhibitor, VX-765 - CAS 273404-37-8 - Calbiochem

531372
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Empirical FormulaCAS #
C₂₄H₃₃ClN₄O₆ 273404-37-8

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      Description
      OverviewAn enhanced cell-permeable, non-toxic, orally available masked aspartaldehyde prodrug that is converted to its active metabolite, VRT-043198, both in vitro and in vivo via hydrolytic cleavage by esterases. The active metabolite displays anti- inflammatory and anticonvulsant properties. Binds to the active site of caspase-1 and caspase-4 with high affinity to inhibit their activity (Ki = 800 pM and 600 pM, respectively). Does not affect the activities of trypsin, cathepsin B and has much reduced effect on other caspases (Ki = 100 nM to 21.5 µM) and granzyme B (Ki = 900 nM). Recently shown to inhibit pyroptosis and prevent CD4 T-cell death by HIV-1. Also shown to block the release of lipopolysaccharide- induced IL-1β and IL-18 in human PBMC (IC50 = 700 pM). Blocks Staphalococcus aureus - Cowen strain I-stimulated production of IL-1β, IL-18, and IFN-γ in human PBMCs (IC50 = 870 nM and 2.8 and 5.6 µM, respectively), but does not affect the TNF-α levels (IC50 > 50 µM). Appears to cross the blood brain barrier to block seizure-induced IL-1β production and delay the onset and reduces the duration of seizures in rats (50 mg/kg, i.p.).

      Please note that the molecular weight for this compound is batch-specific due to variable water content.
      Catalogue Number531372
      Brand Family Calbiochem®
      Synonyms(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, (S)-1-((S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide, (S)-1-((S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide, VX765
      References
      ReferencesDoitsh, G., et al. 2014. Nature 505, 509.
      Wannamaker, W., et al. 2007. J. Pharmacol. Exp. Ther. 321, 509.
      Ravizza, T., et al. 2006. Epilepsia 47, 1160.
      Stack, J.H., et al. 2005. J. Immunol. 175, 2630.
      Product Information
      CAS number273404-37-8
      FormWhite solid
      Hill FormulaC₂₄H₃₃ClN₄O₆
      ReversibleY
      Quality LevelMQ100
      Applications
      Biological Information
      Primary Targetcaspase-1/4
      Purity≥98% by HPLC
      Physicochemical Information
      Cell permeableY
      Dimensions
      Materials Information
      Toxicological Information
      Safety Information according to GHS
      Safety Information
      Product Usage Statements
      Storage and Shipping Information
      Ship Code Shipped at Ambient Temperature or with Blue Ice or with Dry Ice
      Toxicity Standard Handling
      Storage -20°C
      Protect from Light Protect from light
      Protect from Moisture Protect from moisture
      Do not freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 1 month at -20°C.
      Packaging Information
      Packaged under inert gas Packaged under inert gas
      Transport Information
      Supplemental Information
      Specifications

      Documentation

      Caspase-1/4 Inhibitor, VX-765 - CAS 273404-37-8 - Calbiochem SDS

      Title

      Safety Data Sheet (SDS) 

      References

      Reference overview
      Doitsh, G., et al. 2014. Nature 505, 509.
      Wannamaker, W., et al. 2007. J. Pharmacol. Exp. Ther. 321, 509.
      Ravizza, T., et al. 2006. Epilepsia 47, 1160.
      Stack, J.H., et al. 2005. J. Immunol. 175, 2630.
      Data Sheet

      Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

      Revision31-July-2014 JSW
      Synonyms(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, (S)-1-((S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide, (S)-1-((S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)pyrrolidine-2-carboxamide, VX765
      DescriptionThe cell-permeable prodrug of the caspase-1/4-selective inhibitor VRT-43198 (Ki in nM = <0.6/Caspase-4, 0.8/Caspase-1, 100/Caspase-8, 560/Caspase-6, 1,030/Caspase-9, 9,000/Granzyme B, 16,000/Caspase-7, 21,500/Caspase-3; IC50 >100 µM against Cathepsin B & Trypsin). In addition to inhibiting LPS-induced IL-1β production in primary human PBMC cultures (IC50 ~1 µM), VX-765 is also effective in preventing HIV infection-induced IL-1β production and pyroptosis of CD4 T cells in human lymphoid aggregate cultures (HLAC; CD4 population = 29.2% in non-infected control cultures, 8.3% vs. 30.2% in infected cultures with or without 5 µM VX-765). VX-765 is orally available in mice (Blood Cmax = 0.78 µg/mL = 1.53 µM; Tmax = 1.0 h; AUClast = 2.06 µg · h/mL; 84 mg/kg, p.o.) and shown to display in vivo anti-inflammatory efficacy against LPS-induced plasma IL-1β production (EDmax = 100 mg/kg, p.o.), Oxazolone-induced delayed-type hypersensitivity (EDmax = 50 mg/kg, p.o.), collagen-induced arthritis (EDmax = 100 mg/kg, p.o.). When administered via intraperitoneal injection, VX-765 is also demonstrated to suppress the severity of seizure induction (EDmax = 50 mg/kg i.p.) among rats receiving kainic acid via intracerebroventricular injection.
      FormWhite solid
      Intert gas (Yes/No) Packaged under inert gas
      CAS number273404-37-8
      Purity≥98% by HPLC
      SolubilityDMSO (100 mg/ml). Use only fresh DMSO for reconstitution.
      Storage -20°C
      Protect from moisture
      Protect from light
      Do Not Freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 1 month at -20°C.
      Toxicity Standard Handling
      ReferencesDoitsh, G., et al. 2014. Nature 505, 509.
      Wannamaker, W., et al. 2007. J. Pharmacol. Exp. Ther. 321, 509.
      Ravizza, T., et al. 2006. Epilepsia 47, 1160.
      Stack, J.H., et al. 2005. J. Immunol. 175, 2630.