1. Apoptosis
  2. Caspase

VX-765 (Synonyms: Belnacasan)

Cat. No.: HY-13205 Purity: 99.46%
Handling Instructions

VX-765 is an orally active IL-converting enzyme/caspase-1 inhibitor, inhibits IL-1β release with similar potency in PBMCs from FCAS (IC50=0.99±0.29 μM) and control (IC50=1.1±0.61 μM) subjects.

For research use only. We do not sell to patients.
VX-765 Chemical Structure

VX-765 Chemical Structure

CAS No. : 273404-37-8

Size Price Stock Quantity
Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO USD 94 In-stock
5 mg USD 84 In-stock
10 mg USD 119 In-stock
50 mg USD 300 In-stock
100 mg USD 540 In-stock
200 mg   Get quote  
500 mg   Get quote  

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Customer Review

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

VX-765 is an orally active IL-converting enzyme/caspase-1 inhibitor, inhibits IL-1β release with similar potency in PBMCs from FCAS (IC50=0.99±0.29 μM) and control (IC50=1.1±0.61 μM) subjects.

IC50 & Target

Caspase-1[1]

In Vitro

VX-765 inhibits the release of LPS-induced IL-1β and IL-18 by human PBMCs with an IC50 of ~0.7 μM and reduces inflammatory response in murine models of inflammatory disease[1]. VX-765 is a potent, specific inhibitor of the caspase-1 subfamily[2].

In Vivo

VX-765 doses 50, 100, and 200 mg/kg significantly (p<0.05) reduces serum IL-1β levels by as much as 60%, whereas 25 mg/kg has a smaller effect (~35% inhibition) that is not statistically significant. It is noteworthy that the effect of VX-765 on the release of IL-1β induced by LPS reached a plateau at 100 mg/kg. VX-765 (25, 50, and 100 mg/kg × 2) significantly reduces ear edema. VX-765 also dose-dependently reduces the concentrations of cytokines, chemokines, and inflammatory mediators in the ear biopsy samples[2]. VX-765 at doses of 25, 50, and 200 mg/kg significantly delays the time to seizure onset by 1.5- to twofold (p<0.01), reduces the number of seizures by 40% (p<0.01) and the total time spent in EEG seizure activity by 30 to 50% (p<0.01)[3].

Clinical Trial
References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 1.9646 mL 9.8232 mL 19.6464 mL
5 mM 0.3929 mL 1.9646 mL 3.9293 mL
10 mM 0.1965 mL 0.9823 mL 1.9646 mL
Please refer to the solubility information to select the appropriate solvent.
Kinase Assay
[2]

Enzyme inhibition is assayed by tracking of the rate of hydrolysis of an appropriate substrate labeled with either p-nitroaniline or aminomethyl coumarin (AMC) as follows: ICE/caspase-1, suc-YVAD-p-nitroanilide; caspase-4, Ac-WEHD-AMC; caspase-6, Ac-VEID-AMC; caspase-3, -7, -8, and -9, Ac-DEVD-AMC; and granzyme B, Ac-IEPD-AMC. Enzymes and substrates are incubated in a reaction buffer [10 mM Tris, pH 7.5, 0.1% (w/v) CHAPS, 1 mM dithiothreitol, and 5% (v/v) DMSO] for 10 min at 37°C. Glycerol is added to the buffer at 8% (v/v) for caspase-3, -6, and -9 and granzyme B to improve stability of enzymes. The rate of substrate hydrolysis is monitored using a fluorometer. Assays for cathepsin B and trypsin are performed[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

VX-765 is solubilized in DMSO and stored, and then diluted with RPMI 1640 complete medium (DMSO 0.2%) before use[1].

A total of 2×105 cells/well (100 μL cell suspension) is distributed in triplicate in flat-bottom 96-well plates. Either 50 μL of VX-765 (40 μM in RPMI 1640 complete medium containing 0.2% DMSO) or vehicle control is added to appropriate wells. Following a 30-min incubation at 37°C, 50 μL of LPS diluted in RPMI 1640 complete medium is added at final concentrations varying from 0.001 to 10 ng/mL. Cells are returned to a 37°C incubator. At 4 h after LPS addition, 75 μL of supernatant is removed from wells, cleared by centrifugation for 5 min at 1500 rpm, and stored at 4°C until assayed. Cells are returned to a 37°C incubator until 24 h after LPS addition, at which time 100 μL of supernatant is removed, cleared by centrifugation, and stored at 4°C. Supernatants are tested using ELISA kits for IL-1β, IL-6, IL-18, and IL-1α[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[2][3]

VX-765 is prepared in 25% Cremophor EL in water (Mice)[2].
VX-765 is prepared in 20% Cremophor (Rats)[3].

Mice[2]
Single doses of VX-765 (10, 21, 43, and 84 mg/kg) in vehicle (25% Cremophor EL in water) are administered via oral gavage. Blood samples (approximately 0.25-0.3 mL) are collected before dose administration and 0.167, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h after dosing via the retroorbital sinus and processed for plasma. A high-performance liquid chromatography/mass spectrometry methodology is used to determine the concentration of VX-765 and VRT-043198 in plasma samples. Noncompartmental analysis is carried out using WinNonlin Pro, version 4.0.1.
Rats[3]
Male Sprague-Dawley rats (250-280 g) are used. VX-765 (25, 50, 200 mg/kg) is dissolved in 20% Cremophor and injected ip in rats once a day for 3 consecutive days. On the fourth day, rats received VX-765, 45 min and 10 min before intrahippocampal injection of kainic acid. Respective controls are similarly injected with vehicle before kainic acid. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

509.0

Formula

C₂₄H₃₃ClN₄O₆

CAS No.

273404-37-8

SMILES

ClC1=C(N)C=CC(C(N[[email protected]@H](C(C)(C)C)C(N2[[email protected]](C(N[[email protected]]3CC(O[[email protected]]3OCC)=O)=O)CCC2)=O)=O)=C1

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 27 mg/mL

VX-765 is dissolved in DMSO as a stock and then diluted by sesame oil[4].
VX-765 is dissolved in 20% cremophor[5].

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

References

Purity: 99.46%

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Product Name:
VX-765
Cat. No.:
HY-13205
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