VRT-043198
目录号 : GC63256
VRT-043198 是 VX-765 (Belnacasan) 的活性代谢物，是有效的、选择性的、能透过血脑屏障的 caspase-1 的抑制剂。VRT-043198 对 caspase-1 和 caspase-4 的 Ki 值分别为 0.8 nM 和 0.6 nM。
Cas No.:244133-31-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
VRT-043198, the drug metabolite of VX-765 (Belnacasan), is a potent, selective and blood-brain barrier permeable inhibitor of interleukin-converting enzyme/caspase-1 subfamily caspases. VRT-043198 exhibits Ki values of 0.8 nM and 0.6 nM for ICE/caspase-1 and caspase-4, respectively[1].
VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9[1].VRT043198 inhibits the release of interleukin (IL)-1β and IL-18, but it has little effect on the release of several other cytokines, including IL-1α, tumor necrosis factor-, IL-6 and IL-8. VRT-043198 inhibited IL-1β release from both PBMCs (n = 8) and whole blood (n = 4) with IC50 values of 0.67±0.55 and 1.9±0.80 nM, respectively[1].VRT-043198 lacks potent antiapoptotic activity[1].
VX-765 is converted rapidly to VRT-043198 under the action of plasma and liver esterases and also much more slowly in aqueous solution[1].VX765 reduces disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation[1].VX765 (25, 50, 100, or 200 mg/kg) inhibits lipopolysaccharide-induced cytokine secretion[1].
[1]. Woods Wannamaker, 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.
| Cas No. | 244133-31-1 | SDF | |
| 分子式 | C22H29ClN4O6 | 分子量 | 480.94 |
| 溶解度 | DMSO : 180 mg/mL (374.27 mM; Need ultrasonic)|Methanol : 12.5 mg/mL (25.99 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0793 mL | 10.3963 mL | 20.7926 mL |
| 5 mM | 0.4159 mL | 2.0793 mL | 4.1585 mL |
| 10 mM | 0.2079 mL | 1.0396 mL | 2.0793 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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VRT-043198 Ameliorates Surgery-Induced Neurocognitive Disorders by Restoring the NGF and BNDF Expression in Aged Mice
Neuropsychiatr Dis Treat 2022 May 16;18:1027-1037.PMID:35607505DOI:10.2147/NDT.S364250.
Background: Perioperative neurocognitive disorders (PND) are common surgical complications in the elderly. Pyroptosis-associated inflammation has been suggested to participate in a series of neurocognitive diseases, including Alzheimer's disease. Given that VRT-043198 can reportedly inhibit caspase-1-induced pyroptosis, this study sought to determine whether VRT-043198 reduced PND in a mouse model following abdominal exploratory laparotomy. Methods: 20-month-old male C57/BL mice were used to establish an abdominal exploratory laparotomy (AEL) model of PND. VRT-043198 (1, 10 and 100 mg/kg) was administered intraperitoneally immediately after surgery. Thirty days post-surgery, the mice were evaluated in the Morris water maze test. Their number of neurons, neurotrophin nerve growth factor (NGF) levels and brain-derived neurotrophic factor (BDNF) were measured. In the hippocampus, A1-type astrocytes and M1-type microglia were assessed using an immunofluorescence assay and Western blot, respectively. Caspase-1 activity, IL-1β, IL-18, and PPAR-γ were also measured 24h after surgery. Results: VRT-043198 administration increased the time to cross the platform and increased the ratio of distance and time in the targeted quadrant after surgery. Furthermore, it was found that VRT-043198 restored neuronal amount, increased NGF and BDNF and decreased the number of A1-type astrocytes and M1-type microglia. VRT-043198 also attenuated caspase-1 activity, downregulated IL-1β and IL-18, but increased PPAR-γ 24h post-surgery. Conclusion: VRT-043198 improved PND in aged mice after abdominal exploratory laparotomy by restoring the NGF and BNDF expression. These results indicate that VRT-043198 may be a potential therapy for PND.
VX765 alleviates dextran sulfate sodium-induced colitis in mice by suppressing caspase-1-mediated pyroptosis
Int Immunopharmacol 2022 Jan;102:108405.PMID:34865993DOI:10.1016/j.intimp.2021.108405.
Inflammatory bowel disease (IBD) is an autoimmune disease involving intestinal tissue. IBD activates a series of cell death pathways. Pyroptosis is recently identified as a critical cell death pathway in IBD associated with the activation of caspase-1. VX765 is a caspase-1 inhibitor that can be converted to VRT-043198 in vivo. This study was designed to explore the therapeutic effect of VX765 on colitis using a dextran sulfate sodium (DSS)-induced colitis model in mice. In this research, the caspase-1 inhibitor on inflammatory, pyroptosis, apoptosis, macrophage activation, and intestinal barrier were investigated. We found that administration of VX765 attenuated body weight loss, colonic shortening, and colonic pathological injury in mice. Our study also revealed a therapeutic effect of VX765 on colitis in a dose-dependent manner. VX765 inhibited pyroptosis by curbing the Caspase-1/GSDMD pathway and its downstream key inflammatory cytokines--IL-1β and IL-18. These results indicated that VX765 might have a dose-dependent therapeutic effect on DSS-induced colitis in mice.
CASP orter: A Novel Inducible Human CASP1/NALP3/ASC Inflammasome Biosensor
J Inflamm Res 2022 Feb 19;15:1183-1194.PMID:35221708DOI:10.2147/JIR.S333725.
Background: Following our 2015 elucidation of the CASP1/NALP3 inflammasome mechanism of glucocorticoid (GC)-resistance in pediatric acute lymphoblastic leukemia (ALL) patients, we engineered a cell-based CASP1/NALP3 reporter system suitable for high-throughput screening (HTS) of small molecule libraries, with the purpose of identifying compounds capable of inhibiting the CASP1/NALP3 inflammasome and synergizing with GC drugs for the treatment of GC-resistant ALL patients and various autoinflammatory diseases. Methods: A Dox-controlled system was utilized to induce the expression of the ASC transgene in HEK293 cells while simultaneously overexpressing NLRP3 and CASP1. ASC/CASP1/NALP3 inflammasome complex formation was confirmed by co-immunoprecipitation (co-IP) experiments. Next, a LV fluorescence-based biosensor (CASPorter) was transduced in the HEK293-iASC-NLRP3/CASP1 cell line to monitor the real-time activation of CASP1/NALP3 inflammasome in live cells. The applicability and effectiveness of the CASPorter cell line were tested by co-treatment with Dox and four known CASP1/NLRP3 inhibitors (MCC950, Glyburide, VX-765 and VRT-043198). Inflammasome activation and inhibitions were assessed by Western blotting, fluorescence microscopy and flow cytometry (FC) methods. Results: Dox treatment significantly induced ASC expression and increased levels of cleaved and catalytically active CASP1, co-IPs further demonstrated that CASP1 was pulled-down with NLRP3 in HEK293-iASC-NLRP3/CASP1 cells after induction of ASC by Dox treatment. In HEK293-iASC-NLRP3/CASP1-CASPorter cell system, cleavage of the CASP1 consensus site (YVAD) in the CASPorter protein after Dox treatment causing excitation/emission of green fluorescence and the 71% GFP+ cell population increase quantified by FC (78.1% vs 6.90%). Dox-induced activation of the NLRP3 inflammasome was dose-dependently inhibited by Dox co-treatment with four known CASP1/NLRP3 inhibitors. Conclusion: We have established a cell-based CASP1/NLRP3 inflammasome model, utilizing a fluorescence biosensor as readout for qualitatively observing and quantitatively determining the activation of caspase 1 and NLRP3 inflammasomes in living cells and easily define the inhibitory effect of inhibitors with high efficacy.
Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited
Org Biomol Chem 2017 Sep 13;15(35):7456-7473.PMID:28837200DOI:10.1039/c7ob01403a.
As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and biopharmaceutical profile, acylsulfonamides were explored as carboxylate isosteres for caspase inhibitors. Acylsulfonamide analogues of the clinically investigated caspase-1 inhibitor VRT-043198 and of the pan-caspase inhibitor Z-VAD-CHO were synthesized. The isostere-containing analogues with an aldehyde warhead had inhibitory potencies comparable to the carboxylate references. In addition, the conformational and tautomeric characteristics of these molecules were determined using 1H- and 13C-based NMR. The propensity of acylsulfonamides with an aldehyde warhead to occur in a ring-closed conformation at physiological pH significantly increases the sensitivity to hydrolysis of the acylsulfonamide moiety, yielding the parent carboxylate containing inhibitors. These results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter. Finally, inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays.
Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity
Int J Mol Sci 2023 Feb 14;24(4):3801.PMID:36835212DOI:10.3390/ijms24043801.
To study the relationship between caspase-1/4 and reperfusion injury, we measured infarct size (IS) in isolated mouse hearts undergoing 50 min global ischemia/2 h reperfusion. Starting VRT-043198 (VRT) at reperfusion halved IS. The pan-caspase inhibitor emricasan duplicated VRT's protection. IS in caspase-1/4-knockout hearts was similarly reduced, supporting the hypothesis that caspase-1/4 was VRT's only protective target. NLRC4 inflammasomes activate caspase-1. NLRC4 knockout hearts were not protected, eliminating NLRC4 as caspase-1/4's activator. The amount of protection that could be achieved by only suppressing caspase-1/4 activity was limited. In wild-type (WT) hearts, ischemic preconditioning (IPC) was as protective as caspase-1/4 inhibitors. Combining IPC and emricasan in these hearts or preconditioning caspase-1/4-knockout hearts produced an additive IS reduction, indicating that more protection could be achieved by combining treatments. We determined when caspase-1/4 exerted its lethal injury. Starting VRT after 10 min of reperfusion in WT hearts was no longer protective, revealing that caspase-1/4 inflicted its injury within the first 10 min of reperfusion. Ca++ influx at reperfusion might activate caspase-1/4. We tested whether Ca++-dependent soluble adenylyl cyclase (AC10) could be responsible. However, IS in AC10-/- hearts was not different from that in WT control hearts. Ca++-activated calpain has been implicated in reperfusion injury. Calpain could be releasing actin-bound procaspase-1 in cardiomyocytes, which would explain why caspase-1/4-related injury is confined to early reperfusion. The calpain inhibitor calpeptin duplicated emricasan's protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1/4 and calpain may share the same protective target.