Dapansutrile
(Synonyms: 3-methanesulfonyl Propanenitrile) 目录号 : GC34555
An NLRP3 inflammasome inhibitor
Cas No.:54863-37-5
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Dapansutrile is a β-sulfonyl nitrile inhibitor of the NLRP3 inflammasome that inhibits the release of IL-1β and decreases caspase-1 levels in LPS-stimulated J774A.1 murine macrophages, human monocyte derived macrophages (HMDMs), and primary human blood neutrophils without affecting TNF-α release.1 It is selective for NLRP3 over NLRP4 and AIM2 inflammasomes at concentrations up to 100 μM. Dapansutrile inhibits ASC oligomerization and NLRP3 association with caspase-1 and ASC in LPS- and nigericin-stimulated J774A.1 cells. In vivo, Dapansutrile reduces myeloperoxidase (MPO), CXCL1, and IL-6 levels in peritoneal fluid as well as IL-1β levels in liver, lung, spleen, and skeletal muscle in a mouse model of LPS-induced systemic inflammation. It decreases oxidized glutathione and oxaloacetate and increases reduced glutathione, α-ketoglutarate, and citrate levels, markers of oxidative metabolism, in muscle in a mouse model of LPS-induced systemic inflammation. Dapansutrile also reduces IL-1β release in blood monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), an autoinflammatory disorder characterized by gain-of-function mutations in NLRP3.
1.Marchetti, C., Swartzwelter, B., Gamboni, F., et al.OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammationProc. Natl. Acad. Sci. USA115(7)E1530-E1539(2018)
| Cas No. | 54863-37-5 | SDF | |
| 别名 | 3-methanesulfonyl Propanenitrile | ||
| Canonical SMILES | N#CCCS(=O)(C)=O | ||
| 分子式 | C4H7NO2S | 分子量 | 133.17 |
| 溶解度 | DMSO : ≥ 125 mg/mL (938.65 mM) | 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 7.5092 mL | 37.546 mL | 75.092 mL |
| 5 mM | 1.5018 mL | 7.5092 mL | 15.0184 mL |
| 10 mM | 0.7509 mL | 3.7546 mL | 7.5092 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Dapansutrile ameliorated chondrocyte inflammation and osteoarthritis through suppression of MAPK signaling pathway
Hum Exp Toxicol 2022 Jan-Dec;41:9603271221145401.PMID:36508695DOI:10.1177/09603271221145401.
Introduction: Osteoarthritis (OA) is one of the most common joint diseases in the elderly population. Proinflammatory cytokines, such as Interleukin-1β (IL-1β), play an important role in the development and progression of OA. Dapansutrile is a specific inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome and exhibits anti-inflammatory properties. Methods: In this study, we investigated the protective effect and the underlying mechanism of Dapansutrile on cartilage degeneration in vitro and in vivo. In the present study, chondrocytes were isolated from rats and then were treated with Dapansutrile. After that, the expression of (Cox-2, inducible nitric oxide synthase (iNOS), Mmp-3, Mmp-9, Mmp-13 and IL-10) were evaluated at RNA level, then the expression of (COX-2, MMP-3, MMP-9, MMP-13, SOX-9 and COL2) were evaluated at protein level. Subsequently, the activation of the mitogen-activated protein kinase (MAPK) pathway was tested using western blotting (WB). Additionally, the rat OA model was developed to evaluate the protective effects of Dapansutrile in vivo. Results: The results showed that Dapansutrile had no obvious cytotoxicity on rat chondrocytes at 24 h (0, 1, 2, 5 and 10 μM). Dapansutrile significantly decreased IL-1β-induced upregulation of COX2, iNOS, matrix metalloproteinase 3 (MMP3), 9 (MMP9) and 13 (MMP13), and reversed IL-1β-induced the downregulation of IL-10, SOX9 and COL2. Dapansutrile also inhibited IL-1β-induced upregulation of the MAPK signaling pathway by downregulating the expression levels of phospho-ERK, and phospho-P38 in a concentration dependent manner. In addition, Dapansutrile exhibited protective effects in rat OA model with lower Mankin's score and Osteoarthritis Research Society International (OARSI) score. Conclusion: Our study suggested that Dapansutrile effectively inhibited chondrocyte inflammation by suppressing MAPK signaling pathway in vitro, and ameliorated cartilage degeneration in vivo, indicating an anti-inflammatory effect in OA treatment.
The NLRP3 Inflammasome Inhibitor Dapansutrile Attenuates Cyclophosphamide-Induced Interstitial Cystitis
Front Immunol 2022 Jun 3;13:903834.PMID:35720309DOI:10.3389/fimmu.2022.903834.
Interstitial cystitis (IC)/bladder pain syndrome (BPS), hereafter referred together as IC, is a clinical syndrome characterized by sterile inflammation in the bladder. While the etiology and pathophysiology of IC remain unclear, it may involve autoimmunity in light of the significant role played by the NLRP3 inflammasome. However, the effect of NLRP3 inhibitors including Dapansutrile (Dap) on IC had not been explored previously. Here, we investigated the effect of Dap in the cyclophosphamide (CYP)-induced experimental mouse model of IC, which results in functional and histological alterations confined to the urinary bladder (UB) comparable to that of clinical IC. CYP-induced mice treated with Dap exhibited improved UB pathology and reductions in inflammation scores and the frequency and the number of mast cells and neutrophils, relative to mice that received CYP alone. Dap- and CYP-treated mice also exhibited infiltration of T cells in the spleen and iliac lymph nodes (ILNs) and a concurrent significant decrease (p<0.01) in CXCR3+CD8+ T cells in the UB, induction of systemic and mucosal dendritic cells (DCs), and reduced levels of systemic proinflammatory cytokines, as compared to CYP alone. We also observed decreases in the expression of several signaling pathways regulators, including interleukin-1 beta (IL-1β), NLRP3, caspase-1, nuclear factor kappa B (NF-κB), and inducible nitric oxide synthase (iNOS) in the UB of CYP- and Dap-treated mice, relative to those receiving CYP alone. Taken together, these results suggest that Dap suppresses IC through the reduction of CXCR3+T cells, mast cells, and neutrophils in the UB and induces DCs as a protective measure. The present study identifies the mechanisms underlying the amelioration of IC by the NLRP3 inhibitor Dap and may provide an avenue for a potential therapeutic agent for the treatment of IC.
The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer's disease
Proc Natl Acad Sci U S A 2020 Dec 15;117(50):32145-32154.PMID:33257576DOI:10.1073/pnas.2009680117.
Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer's disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using Dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.
Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion
Proc Natl Acad Sci U S A 2021 Mar 9;118(10):e2000915118.PMID:33649199DOI:10.1073/pnas.2000915118.
Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by Dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.
OLT1177 (Dapansutrile), a Selective NLRP3 Inflammasome Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis
Front Immunol 2019 Nov 1;10:2578.PMID:31736980DOI:10.3389/fimmu.2019.02578.
IL-1β and IL-18 are pro-inflammatory cytokines that are linked to inflammation. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the maturation and secretion of IL-1β and IL-18 and, thus, plays a key role in the pathogenesis of many inflammatory conditions, including multiple sclerosis (MS). OLT1177™ (Dapansutrile) is a newly developed drug that is safe in humans and inhibits specifically the NLRP3 inflammasome. In the present study, we investigated whether OLT1177 exerts therapeutic effects in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that EAE mice fed an OLT1177-enriched diet prophylactically were significantly protected against functional deficits and demyelination in the spinal cord. We also demonstrated that prophylactic oral administration of OLT1177 led to marked reduction (~2- to 3-fold) in the protein levels of IL-1β and IL-18, as well as, IL-6 and TNFα, in the spinal cord of EAE mice. Moreover, prophylactic oral administration of OLT1177 significantly attenuated the infiltration of CD4 T cells and macrophages in the spinal cord. We also demonstrated that oral administration of OLT1177, starting at disease onset, resulted in significant amelioration of the clinical signs of EAE. Overall, these first data suggest that OLT1177 could have clinical benefit for the treatment of MS in humans.