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

531372
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      Overview

      Replacement Information

      Key Specifications Table

      Empirical FormulaCAS #
      C₂₄H₃₃ClN₄O₆ 273404-37-8

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      5.31372.0001
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          Glass bottle 10 mg
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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
          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

          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 light
          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.
          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.