SB 203580
(Synonyms: 4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)-1H-咪唑,SB 203580; RWJ 64809) 目录号 : GC13595
SB 203580是p38-MAPK（有丝分裂原活化蛋白激酶）通路的特异性抑制剂
Cas No.:152121-47-6
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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| Cell experiment [1]: | |
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Cell lines |
MDA-MB-231 human breast cancer cell line |
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Preparation Method |
Cells were treated at the logarithmic phase of the growth with various doses of SB 203580 (0.1, 0.5, 1, 5, 10, 25, 50, 100 µM) for 24 h |
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Reaction Conditions |
0.1, 0.5, 1, 5, 10, 25, 50, 100 µM for 24 h |
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Applications |
SB 203580 did not cause significant cytotoxicity on human MDA-MB-231 breast cancer cell line at low concentrations (0.1-10 µM) as compared to vehicle-treated (0.5% DMSO) control cells. However, the cytotoxic effects of both inhibitors were observed with higher concentrations of 25, 50 and 100 µM.. |
| Animal experiment [2]: | |
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Animal models |
Male Balb/c mice |
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Preparation Method |
Treatments with 2% DMSO alone or SB 203580 dissolved in 2% DMSO were given 1 h before and 1 h and 24 h after DENV infection intravenously. The volume of all injections was 0.4 ml. At 7 days after infection, the mice were euthanized with an overdose intraperitoneal injection of sodium pentobarbital anesthesia. |
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Dosage form |
5 mg/kg/d for 7 days, infection intravenously |
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Applications |
After the DENV-infected mice were treated with SB 203580, their liver AST levels were significantly reduced, but the changes in ALT were failed to reach statistical significance |
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References: [1]: Duzgun SA, Yerlikaya A, Zeren S, Bayhan Z, Okur E, Boyaci I. Differential effects of p38 MAP kinase inhibitors SB 203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology. 2017;69(4):711-24. | |
SB 203580 is a specific inhibitor of p38-MAPK (Mitogen-activated Protein Kinase) pathway [1,2]. SB 203580 inhibits p38 kinase in a manner competitive with ATP with a Ki of 21 nm [2].
SB 203580 inhibit the proliferation of human breast cancer cell line MDA-MB-231 with the IC50 value of was 85.1 µM [3]. SB 203580 inhibited IL-10 production by monocytic WEHI 274.3 cells expressing WT-p38α MAPK in a dose-dependent manner with greater than 95% inhibition at 5 µm and with an IC50 of 0.1µM [4]. IL-2-induced proliferation of primary human T cells, murine CT6 T cells, or BAF F7 B cells is prevented by the p38 MAP kinase inhibitor SB 203580 with an IC50 of 3-5µM [5].
SB-203580 demonstrated moderate to high clearance in all species tested in vivo, with non-linear elimination observed in the rat at plasma concentrations > 1000ng ml -1. Although good solution bioavailability was observed in non-rodents (78% in dog, 32% in monkey), lower and more variable bioavailability was observed in the rat and mouse (3-48%) [6]. SB 203580 treatment significantly improve the white blood cell (WBC) and platelet counts decreased significantly in the DENV-infected mice, suggesting leucopenia and thrombocytopenia, respectively [7].
SB 203580是p38-MAPK（有丝分裂原活化蛋白激酶）通路的特异性抑制剂。它以与ATP竞争的方式抑制p38激酶，Ki值为21纳摩尔。
SB 203580可以抑制人乳腺癌细胞系MDA-MB-231的增殖，其IC50值为85.1微米[3]。在表达WT-p38α MAPK的单核WEHI 274.3细胞中，SB 203580以剂量依赖方式抑制IL-10的产生，在5微米时可达到95%以上的抑制率，并且其IC50为0.1微米[4]。 SB 203580是p38 MAP激酶抑制剂，可以防止IL-2诱导的原代人T细胞、小鼠CT6 T细胞或BAF F7 B细胞增殖，其IC50为3-5µM [5]。
在所有测试的物种中，SB-203580在体内表现出中等到高度的清除能力，在大鼠血浆浓度>1000ng ml -1时观察到非线性消除。尽管非啮齿动物（狗78％，猴子32％）观察到良好的溶液生物利用度，但在大鼠和小鼠中观察到较低且更为不稳定的生物利用度（3-48%）[6]。 SB 203580治疗显着改善了DENV感染小鼠的白细胞计数和血小板计数明显下降，分别提示粒细胞减少和血小板减少[7]。
References:
[1]. Barancik M, Bohacova V, Kvackajova J, Hudecova S, Krizanova O, Breier A: SB 203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci. 2001, 14: 29-36. 10.1016/S0928-0987(01)00139-7.
[2]. Peter R. Young, Megan M. McLaughlin, Sanjay Kumar, et al. Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site. The Journal of Biological Chemistry, 1997, 272(18): 12116-12121.
[3]. Duzgun SA, Yerlikaya A, Zeren S, Bayhan Z, Okur E, Boyaci I. Differential effects of p38 MAP kinase inhibitors SB 203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology. 2017;69(4):711-24.
[4]. Guo, X., R.E. Gerl, and J.W. Schrader. 2003. Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J. Biol. Chem. 278:22237-22242.
[5]. Lali, F. V., Hunt, A. E., Turner, S. J., and Foxwell, B. M. The pyridinyl imidazole inhibitor SB 203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J. Biol. Chem.,275: 7395-7402,?2000
[6]. Ward KW, Prokscht JW, Azzaranot LM, et al. Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase. Xenobiotica 2001; 31: 783-97
[7]. Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Noisakran S, Yenchitsomanus PT, et al. SB 203580 modulates p38 MAPK signaling and Dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One. 2016;11:e0149486.
| Cas No. | 152121-47-6 | SDF | |
| 别名 | 4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)-1H-咪唑,SB 203580; RWJ 64809 | ||
| 化学名 | 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine | ||
| Canonical SMILES | CS(=O)C1=CC=C(C=C1)C2=NC(=C(N2)C3=CC=NC=C3)C4=CC=C(C=C4)F | ||
| 分子式 | C21H16FN3OS | 分子量 | 377.44 |
| 溶解度 | ≥ 18.872mg/mL in DMSO, ≥ 3.28 mg/mL in EtOH with ultrasonic | 储存条件 | Desiccate at 4°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 | 2.6494 mL | 13.2471 mL | 26.4943 mL |
| 5 mM | 0.5299 mL | 2.6494 mL | 5.2989 mL |
| 10 mM | 0.2649 mL | 1.3247 mL | 2.6494 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 | ||||||||||
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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。
SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts
There is debate concerning the involvement of p38 mitogen-activated protein kinase (MAPK) in ischemic preconditioning (PC). At the center of the controversy are data obtained after administration of SB 203580, a specific inhibitor of p38 MAPK. Whereas several studies have reported that SB 203580 abolishes the cardioprotective effect of PC, others claim that this compound is actually cardioprotective against ischemia. Many of these latter observations have been made in isolated myocardial cells. Accordingly the present study was designed to test the effect of SB 203580 in a model of preconditioning in intact rabbit hearts in which infarct size was the end-point. Isolated hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.2 +/- 3.3% of the risk zone. PC with 5 min of global ischemia and 10 min of reperfusion before the 30-min period of ischemia significantly reduced infarct size to 10.2 +/- 2.4% (P < 0.05 vs. control). SB 203580 (2 microM) added to the perfusate for 20 min starting 5 min before the index ischemia totally blocked the protection from PC (27.4 +/- 3.3% infarction). SB 203580 alone had no effect on infarct size (28.6 +/- 4.6% infarction). These results reveal that SB 203580 does not affect infarct size on its own, but selectively blocks preconditioning's anti-infarct effect in the intact rabbit heart.
Effect of SB 203580 on the activity of c-Raf in vitro and in vivo
The inhibition of SAPK2a/p38 (a mitogen activated protein (MAP) kinase family member) by SB 203580 depends on the presence of threonine at residue 106. Nearly all other protein kinases are insensitive to this drug because a more bulky residue occupies this site (Eyers et al., 1998). Raf is one of the few protein kinases that possesses threonine at this position, and we show that SB 203580 inhibits c-Raf with an IC50 of 2 microM in vitro. However, SB 203580 does not suppress either growth factor or phorbol ester-induced activation of the classical MAP kinase cascade in mammalian cells. One of the reasons for this is that SB 203580 also triggers a remarkable activation of c-Raf in vivo (when measured in the absence of the drug). The SB 203580-induced activation of c-Raf occurs without any increase in the GTP-loading of Ras, is not prevented by inhibitors of the MAPK cascade, protein kinase C or phosphatidylinositide 3-kinase, and is not triggered by the binding of this drug to SAPK2a/p38. The paradoxical activation of c-Raf by SB 203580 (and by another structurally unrelated c-Raf inhibitor) suggests that inhibitors of the kinase activity of c-Raf may not be effective as anti-cancer drugs.
SB 203580 inhibits p38 mitogen-activated protein kinase, nitric oxide production, and inducible nitric oxide synthase in bovine cartilage-derived chondrocytes
Nitric oxide (NO) is implicated in a number of inflammatory processes and is an important mediator in animal models of rheumatoid arthritis and in in vitro models of cartilage degradation. The pyridinyl imidazole SB 203580 inhibits p38 mitogen-activated protein (MAP) kinase in vitro, blocks proinflammatory cytokine production in vitro and in vivo, and is effective in animal models of arthritis. The purpose of this study was to determine whether SB 203580 could inhibit p38 MAP kinase activity, NO production, and inducible NO synthase (iNOS) in IL-1 stimulated bovine articular cartilage/chondrocyte cultures. The results indicated that SB 203580 inhibited both IL-1 stimulated p38 MAP kinase activity in isolated chondrocytes and NO production in bovine chondrocytes and cartilage explants with an IC50 value of approximately 1 microM. To inhibit NO production, SB 203580 had to be present in cartilage explant cultures during the first 8 h of IL-1 stimulation, and activity was lost when it was added 24 h following IL-1. SB 203580 did not inhibit iNOS activity, as measured by the conversion of arginine to citrulline, when added directly to cultures where the enzyme had already been induced, but had to be present during the induction period. Using a 372-bp probe for bovine iNOS we demonstrated inhibition of IL-1-induced mRNA by SB 203580 at both 4 and 24 h following IL-1 treatment. The iNOS mRNA levels were consistent with NO levels in 24-h cell culture supernatants of the IL-1-stimulated bovine chondrocytes used to obtain the RNA.
SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1
A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739-746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (IC50 = 0.6 microM), suppresses the activation of MAPKAP kinase-2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin-1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase-2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase-2 in vivo. The specificity of SB 203580 was indicated by its failure to inhibit 12 other protein kinases in vitro, and by its lack of effect on the activation of RK kinase and other MAP kinase cascades in vivo. We suggest that SB 203580 will be useful for identifying other physiological roles and targets of RK and MAPKAP kinase-2.
Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase
1. SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)imidazole) is a potent, selective inhibitor of p38 MAP kinase used extensively as a tool inhibitor in various pharmacological and toxicological models. This study was designed to evaluate the pharmacokinetics of SB-203580 in several preclinical species, both to assist with the interpretation of existing studies and to aid in the design of future studies with this inhibitor. 2. In vitro, SB-203580 was stable in mouse, rat, dog, monkey and human plasma over 24 h. However, species differences in plasma protein binding were observed; SB-203580 was 96-97% bound in human plasma and 78-92% bound in other species. These data suggest that protein binding may influence the results of in vitro studies using SB-203580, particularly when comparing results from different in vitro systems that incorporate plasma components. In vivo, SB-203580) demonstrated moderate to high clearance in all species tested, with non-linear elimination observed in the rat at plasma concentrations > 1,000 ngml(-1). Although good solution bioavailability was observed in non-rodents (78% in dog, 32% in monkey), lower and more variable bioavailability was observed in the rat and mouse (3 -48%). 3. These interspecies differences in bioavailability, and the non-linear pharmacokinetics observed in rat, highlight the importance of monitoring SB-203580 systemic exposure in parallel witb the pharmacological endpoint during in vivo pharmacology