VX-765 纯度:99.99% 500mg

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VX-765 纯度:99.99% 500mg

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货号：HY-13205

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北京朝阳

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商品介绍
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VX-765是VRT-043198的口服前药，是一种有效，选择性的 caspase-1 抑制剂，K_i为0.8 nM。

Description

VX-765 is an oral prodrug of VRT-043198, a potent and selective caspase-1 inhibitor with a K_i of 0.8 nM.

IC₅₀ & Target

Caspase-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].

Solvent & Solubility

In Vitro:

DMSO : ≥ 27 mg/mL (53.05 mM)

* "≥" means soluble, but saturation unknown.

Preparing
Stock Solutions

Concentration Solvent 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.

In Vivo:

1.

Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in saline)

Solubility: ≥ 2.08 mg/mL (4.09 mM); Clear solution
2.

Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% saline

Solubility: ≥ 2.08 mg/mL (4.09 mM); Clear solution
3.

Add each solvent one by one: 10% DMSO 90% corn oil

Solubility: ≥ 2.08 mg/mL (4.09 mM); Clear solution

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.

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]	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]	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	[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.