BIRB 796 (Doramapimod)
(Synonyms: 达马莫德; BIRB 796) 目录号 : GC11497
A potent inhibitor of p38 MAPK
Cas No.:285983-48-4
Sample solution is provided at 25 µL, 10mM.
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EC50: 18 nM for TNF-α in THP-1 cells
The signal transduction pathway leading to the production of TNF-α from stimulated inflammatory cells, while not fully understood, has been shown to be partially regulated by p38 mitogen activated protein (MAP) kinase. The p38 MAP kinase plays a crucial role in regulating the production of proinflammatory cytokines. Blocking this kinase may offer an effective therapy for the treatment of many inflammatory diseases. BIRB 796 is a highly potent inhibitor of p38 MAPK.
In vitro: BIRB 796 is a picomolar inhibitor of human p38 MAP kinase with a 12,000-fold increase in binding affinity. Moreover, BIRB 796 behavors as one of the most potent and slowest dissociating human p38 MAP kinase inhibitors now known [1].
In vivo: In a LPS-stimulated TNF-α synthesis mouse model, a 65% inhibition of TNF-α synthesis was observed when BIRB 796 was dosed orally at 10 mg/kg. In a model of established collagen-induced arthritis using B10.RIII mice, BIRB 796 showed a 63% inhibition of arthritis severity when dosed orally at 30 mg/kg qd [2].
Clinical trial: No clinical efficacy (Crohn’s Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant and dose-dependent decrease of C-reactive protein level was seen transiently after BIRB 796 after 1 week with a return to baseline level over time [3].
References:
[1] Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S, Regan J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol. 2002 Apr;9(4):268-72.
[2] Regan J, Breitfelder S, Cirillo P, Gilmore T, Graham AG, Hickey E, Klaus B, Madwed J, Moriak M, Moss N, Pargellis C, Pav S, Proto A, Swinamer A, Tong L, Torcellini C. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J Med Chem. 2002 Jul 4;45(14):2994-3008.
[3] Schreiber S, Feagan B, D'Haens G, Colombel JF, Geboes K, Yurcov M, Isakov V, Golovenko O, Bernstein CN, Ludwig D, Winter T, Meier U, Yong C, Steffgen J; BIRB 796 Study Group. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006 Mar;4(3):325-34.
| Cell experiment: [1] | |
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Cell lines |
MM.1S cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
400 nM, 24 hours |
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Applications |
BIRB 796 inhibited baseline and Dex-induced phosphorylation of both p38 MAPK and Hsp27 in MM.1S cells. Although MM.1S cell proliferation was strongly inhibited by Dex alone at 24–72 h, BIRB 796 significantly enhanced its growth inhibition. Cell cycle profiling suggests that BIRB 796 augmented Dex-mediated growth inhibition by enhancing apoptosis (Sub-G1 portion: control = 6.1%, BIRB 796 alone = 8.0%, Dex alone = 34.7%, BIRB 796 plus Dex = 45.7%). |
| Animal experiment: [2] | |
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Animal models |
Male Crlj:CD1(ICR)mice |
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Dosage form |
Oral administration; 250, 500 or 1000 mg/kg |
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Applications |
To characterize the mechanism(s) responsible for the hepatotoxicy, a toxicogenomic analysis was performed using total RNA prepared from the liver from mice treated with BIRB-796. A variety of genes were up-regulated or down-regulated by BIRB‐796 at all dosages (250, 500 and 1000 mg kg−1), including the genes of Alpha-2-HS-glycoprotein, Apolipoprotein A-IV, CD5 antigen-like, Cathepsin S and so on. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Yasui H, Hideshima T, Ikeda H, et al. BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. British journal of haematology, 2007, 136(3): 414-423. [2] Iwano S, Asaoka Y, Akiyama H, et al. A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor. Journal of Applied Toxicology, 2011, 31(7): 671-677. | |
| Cas No. | 285983-48-4 | SDF | |
| 别名 | 达马莫德; BIRB 796 | ||
| 化学名 | 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea | ||
| Canonical SMILES | CC1=CC=C(C=C1)N2C(=CC(=N2)C(C)(C)C)NC(=O)NC3=CC=C(C4=CC=CC=C43)OCCN5CCOCC5 | ||
| 分子式 | C31H37N5O3 | 分子量 | 527.66 |
| 溶解度 | ≥ 26.4mg/mL in DMSO, ≥ 11.24 mg/mL in EtOH with 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 | 1.8952 mL | 9.4758 mL | 18.9516 mL |
| 5 mM | 0.379 mL | 1.8952 mL | 3.7903 mL |
| 10 mM | 0.1895 mL | 0.9476 mL | 1.8952 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。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet