CAS 273404-37-8|VX-765
Introduction：Basic information about CAS 273404-37-8|VX-765, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
| Common Name | VX-765 | ||
|---|---|---|---|
| CAS Number | 273404-37-8 | Molecular Weight | 508.995 |
| Density | 1.3±0.1 g/cm3 | Boiling Point | 779.0±60.0 °C at 760 mmHg |
| Molecular Formula | C24H33ClN4O6 | Melting Point | / |
| MSDS | / | Flash Point | 424.9±32.9 °C |
Names
| Name | N-(4-Amino-3-chlorobenzoyl)-3-methyl-L-valyl-N-[(2R,3S)-2-ethoxy- 5-oxotetrahydro-3-furanyl]-L-prolinamide |
|---|---|
| Synonym | More Synonyms |
VX-765 BiologicalActivity
| Description | Belnacasan (VX-765) is an oral prodrug of VRT-043198, a potent and selective caspase-1 inhibitor with a Ki of 0.8 nM. |
|---|---|
| Related Catalog | Signaling Pathways >>Apoptosis >>CaspaseResearch Areas >>Inflammation/Immunology |
| Target | Caspase-1 |
| In Vitro | Belnacasan 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]. VBelnacasan is a potent, specific inhibitor of the caspase-1 subfamily[2]. |
| In Vivo | Belnacasan 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 Belnacasan on the release of IL-1β induced by LPS reached a plateau at 100 mg/kg. Belnacasan (25, 50, and 100 mg/kg × 2) significantly reduces ear edema. Belnacasan also dose-dependently reduces the concentrations of cytokines, chemokines, and inflammatory mediators in the ear biopsy samples[2]. Belnacasan 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]. |
| Kinase Assay | 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]. |
| Cell Assay | 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 Belnacasan (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]. |
| Animal Admin | Mice[2] Single doses of Belnacasan (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 Belnacasan 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. Belnacasan (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 receive Belnacasan, 45 min and 10 min before intrahippocampal injection of kainic acid. Respective controls are similarly injected with vehicle before kainic acid. |
| References | [1]. Stack JH, et al. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 2005 Aug 15;175(4):2630-4. [2]. Wannamaker W, 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. [3]. Ravizza T, et al. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia. 2006 Jul;47(7):1160-8. [4]. Xu Y, et al. NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun. 2016 Aug;56:175-86. [5]. Zhuang J, et al. TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2 2',4,4'-tetrabromodiphenyl ether (BDE-47)-treated mice. Brain Behav Immun. 2017 Oct;65:99-110. |
Chemical & Physical Properties
| Density | 1.3±0.1 g/cm3 |
|---|---|
| Boiling Point | 779.0±60.0 °C at 760 mmHg |
| Molecular Formula | C24H33ClN4O6 |
| Molecular Weight | 508.995 |
| Flash Point | 424.9±32.9 °C |
| Exact Mass | 508.208862 |
| PSA | 147.04000 |
| LogP | 0.83 |
| Vapour Pressure | 0.0±2.7 mmHg at 25°C |
| Index of Refraction | 1.589 |
| InChIKey | SJDDOCKBXFJEJB-MOKWFATOSA-N |
| SMILES | CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(NC(=O)c1ccc(N)c(Cl)c1)C(C)(C)C |
| Storage condition | -20℃ |
Synonyms
| vx765 |
| Belnacasan |
| VX-765 |
| N-(4-Amino-3-chlorobenzoyl)-3-methylvalyl-N-[(2R,3S)-2-ethoxy-5-oxotetrahydro-3-furanyl]-L-prolinamide |
| L-Prolinamide, N-(4-amino-3-chlorobenzoyl)-3-methylvalyl-N-[(2R,3S)-2-ethoxytetrahydro-5-oxo-3-furanyl]- |
