VX-765

• 产品号: S2228
• CAS号: 273404-37-8
• 分子式: C24H33ClN4O6
• 分子量: 508.99502
• 保 存: -20°C

产品别名

• 标题: VX-765
• IUPAC标准名: (2S)-1-[(2S)-2-[(4-amino-3-chlorophenyl)formamido]-3,3-dimethylbutanoyl]-N-[(2R)-2-ethoxy-5-oxooxolan-3-yl]pyrrolidine-2-carboxamide
• IUPAC传统名: (2S)-1-[(2S)-2-[(4-amino-3-chlorophenyl)formamido]-3,3-dimethylbutanoyl]-N-[(2R)-2-ethoxy-5-oxooxolan-3-yl]pyrrolidine-2-carboxamide
• 别名: VX765

产品登记号

• CAS号: 273404-37-8

产品性质

• 作用靶点: Caspase
• 成盐信息: Free Base
• 保存条件: -20°C

产品详细信息

详细说明 (English)

Research Area

• Description: Epilepsy

Biological Activity

• Description: VX-765 is a potent and selective inhibitor of caspase-1 with K_i of 0.8 nM.
• Targets: Caspase-1
• IC50: 0.8 nM (K_i) ^[1]
• In Vitro: VX-765 is an orally absorbed prodrug of VRT-043198, which exhibits potent inhibition against ICE/caspase-1 and caspase-4 with Ki of 0.8 nM and less than 0.6 nM, respectively. And VRT-043198 also inhibits IL-1β release from both PBMCs and whole blood with IC50 of 0.67 μM and 1.9 μM, respectively. ^[1]
• In Vivo: In collagen-induced arthritis mouse model, VX-765 (200 mg/kg) inhibits LPS-induced IL-1β production by about 60%, and results in a dose-dependent, statistically significant reduction in the inflammation scores and effective protection from joint changes. ^[1] In vivo, VX-765 blocks kindling epileptogenesis in rats by preventing IL-1β increase in forebrain astrocytes without significant effect on afterdischarge duration. ^[2] In the mouse model of acute seizures, VX-765 (50 mg/kg-200 mg/kg) produces the anticonvulsant effect by delaying the time to onset of the first seizure and decreasing the number of seizures as well as their total duration by average 50% and 64%. ^[3] In adult rats with genetic absence epilepsy (GAERS), VX-765, after the 3rd drug injection, significantly reduces the cumulative duration and number of spike-and-wave discharges (SWDs) by 55% on average by selectively blocking IL-1β biosynthesis. ^[4]
• Clinical Trials: VX-765 is currently in Phase II clinical trials in patients with treatment-resistant partial epilepsy.
• Features: VX-765 is a potent and selective inhibitor of interleukin-converting enzyme/caspase-1.

Protocol

• Protocol: Kinase Assay ^[1]
• Protease Enzyme Assays: 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) dimethyl sulfoxide] for 10 minutes 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.
• Protocol: Animal Study ^[1]
• Animal Models: Collagen-induced arthritis mouse model.
• Formulation: VX-765 is dissolved in 25% Cremophor EL.
• Doses: ≤200 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Wannamaker W, et al. J Pharmacol Exp Ther. 2007, 321(2), 509-516.
• References: [2] Ravizza T, et al. Neurobiol Dis. 2008, 31(3), 327-333.
• References: [3] Maroso M, et al. Neurotherapeutics. 2011, 8(2), 304-315.
• References: [4] Akin D, et al. Neurobiol Dis. 2011, 44(3), 259-269.

参考文献

• Wannamaker W, et al. J Pharmacol Exp Ther. 2007, 321(2), 509-516.
• Ravizza T, et al. Neurobiol Dis. 2008, 31(3), 327-333.
• Maroso M, et al. Neurotherapeutics. 2011, 8(2), 304-315.
• Akin D, et al. Neurobiol Dis. 2011, 44(3), 259-269.