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285983-48-4 分子结构
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3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-{4-[2-(morpholin-4-yl)ethoxy]naphthalen-1-yl}urea

ChemBase编号:2748
分子式:C31H37N5O3
平均质量:527.65718
单一同位素质量:527.28964007
SMILES和InChIs

SMILES:
Cc1ccc(cc1)n1nc(cc1NC(=O)Nc1ccc(OCCN2CCOCC2)c2c1cccc2)C(C)(C)C
Canonical SMILES:
O=C(Nc1cc(nn1c1ccc(cc1)C)C(C)(C)C)Nc1ccc(c2c1cccc2)OCCN1CCOCC1
InChI:
InChI=1S/C31H37N5O3/c1-22-9-11-23(12-10-22)36-29(21-28(34-36)31(2,3)4)33-30(37)32-26-13-14-27(25-8-6-5-7-24(25)26)39-20-17-35-15-18-38-19-16-35/h5-14,21H,15-20H2,1-4H3,(H2,32,33,37)
InChIKey:
MVCOAUNKQVWQHZ-UHFFFAOYSA-N

引用这个纪录

CBID:2748 http://www.chembase.cn/molecule-2748.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-{4-[2-(morpholin-4-yl)ethoxy]naphthalen-1-yl}urea
IUPAC传统名
doramapimod
别名
1-(5-Tert-Butyl-2-P-Tolyl-2h-Pyrazol-3-Yl)-3-[4-(2-Morpholin-4-Yl-Ethoxy)-Naphthalen-1-Yl]-Urea
BIRB 796
CAS号
285983-48-4
PubChem SID
160966196
46506062
PubChem CID
156422

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S1574 external link 加入购物车 请登录

理论计算性质

理论计算性质

JChem ALOGPS 2.1
Acid pKa 11.464863  质子受体
质子供体 LogD (pH = 5.5) 5.068174 
LogD (pH = 7.4) 6.276217  Log P 6.3700423 
摩尔折射率 157.0099 cm3 极化性 60.95927 Å3
极化表面积 80.65 Å2 可自由旋转的化学键
里宾斯基五规则 false 
Log P 5.32  LOG S -5.15 
溶解度 3.75e-03 g/l 

分子性质

分子性质

安全信息 药理学性质 产品相关信息 生物活性(PubChem)
保存条件
-20°C expand 查看数据来源
作用靶点
p38 MAPK expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

DrugBank DrugBank Selleck Chemicals Selleck Chemicals
DrugBank -  DB03044 external link
Drug information: experimental
Selleck Chemicals -  S1574 external link
Research Area
Description Inflammation
Biological Activity
Description BIRB 796 (Doramapimod) is a highly selective p38α MAPK inhibitor to TNF-α with EC50 of 18 nM.
Targets TNF-α
IC50 18 nM (EC50) [1]
In Vitro BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2β, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-α, PKC-β (I and II) and PKC-γ. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. BIRB 796 represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known. [1] BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. [2] BIRB796 also inhibits the activity and the activation of SAPK3/p38γ at a higher concentration than it does in p38α. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. BIRB796 blocks JNK1/2 activation and activity in HEK293 cells, while not inhibits the activation and activity of ERK1/ERK2 in Hela cells. Moreover, the binding of BIRB796 to the p38 MAPKs or JNK1/2 is impairing their phosphorylation by the upstream kinase MKK6 or MKK4 rather than enhancing their dephosphorylation. [3] BIRB 796 blocks baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. BIRB 796 downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1. [4] BIRB-796 has a pyrazole scaffold that places a lipophilic t-butyl group into the lower selectivity site and a tolyl ring into the upper selectivity site. BIRB-796 also inhibits B-Raf and Abl with IC50 of 83?nM and 14.6?μM, respectively. [5]
In Vivo BIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis. [1] BIRB 796 has good pharmacokinetic performance even after oral administration in mice. [2]
Clinical Trials Boehringer Ingelheim has announced the discontinuation of BIRB 796 R&D project in 2005.
Features BIRB 796 is the first p38 MAPK inhibitor to reach phase III clinical trial.
Protocol
Kinase Assay [6]
Procedures for the THP-1 cellular assay for inhibition of LPS-stimulated TNF-α production THP-1 cells are preincubated in the presence and absence of BIRB 796 for 30 min. Cell mixture is stimulated with LPS (1 μg/mL final) and incubation continued overnight (18?24 hours) as above. Supernatant is analyzed for human TNF-α by a commercially available ELISA. Data are combined and analyzed by nonlinear regression using a three parameter logistic model to obtain an EC50 value. BIRB 796 is analyzed in each experiment and the 95% confidence intervals for the EC50 are between 16 and 22 nM.
Animal Study [2]
Animal Models Collagen-induced arthritis in female Balb/c mice
Formulation 70% PEG400 (intravenous) or 100% PEG400 (oral)
Doses 1 mg/kg (intravenous) or 10 mg/kg (oral)
Administration Intravenous injection or by oral
References
[1] Pargellis C, et al. Nat Struct Biol, 2002, 9(4), 268-272.
[2] Regan J, et al. J Med Chem, 2002, 45(14), 2994-3008.
[3] Kuma Y, et al. J Biol Chem, 2005, 280(20), 19472-19479.
[4] Yasui H, et al. Br J Haematol, 2007, 136(3), 414-423.
[5] Dietrich J, et al. Bioorg Med Chem. 2010, 18(15), 5738-5748.
[6] Regan J, et al. J Med Chem, 2003, 46(22), 4676-4686.

专利

专利

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互联网资源

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