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

A cell-permeable prodrug that upon conversion to its active form inhibits caspase-1 and 4 activity (Ki = 800 pM and 600 pM, respectively).

MSDS (material safety data sheet) or SDS, CoA and CoQ, dossiers, brochures and other available documents.

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

Primary Target: caspase-1/4
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Overview

Replacement Information

Key Spec Table

CAS #Empirical Formula
273404-37-8C₂₄H₃₃ClN₄O₆

Products

Catalogue NumberPackaging Qty/Pack
5.31372.0001 Glass bottle 10 mg
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
Global Trade Item Number
Catalogue Number GTIN
5.31372.0001 04055977260304

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 Protect from moisture
Protect from light
-20°C
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.