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1025687-58-4 分子结构
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disodium [6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate

ChemBase编号:72900
分子式:C23H24FN6Na2O9P
平均质量:624.4231642
单一同位素质量:624.11217979
SMILES和InChIs

SMILES:
c1(c(c(cc(c1)Nc1ncc(c(n1)Nc1ccc2c(n1)N(C(=O)C(O2)(C)C)COP(=O)([O-])[O-])F)OC)OC)OC.[Na+].[Na+]
Canonical SMILES:
COc1cc(Nc2ncc(c(n2)Nc2ccc3c(n2)N(COP(=O)([O-])[O-])C(=O)C(O3)(C)C)F)cc(c1OC)OC.[Na+].[Na+]
InChI:
InChI=1S/C23H26FN6O9P.2Na/c1-23(2)21(31)30(11-38-40(32,33)34)20-14(39-23)6-7-17(28-20)27-19-13(24)10-25-22(29-19)26-12-8-15(35-3)18(37-5)16(9-12)36-4;;/h6-10H,11H2,1-5H3,(H2,32,33,34)(H2,25,26,27,28,29);;/q;2*+1/p-2
InChIKey:
HSYBQXDGYCYSGA-UHFFFAOYSA-L

引用这个纪录

CBID:72900 http://www.chembase.cn/molecule-72900.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
disodium [6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate
IUPAC传统名
disodium [6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate
别名
6-[[5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one Sodium Salt Hydrate
Fostamatinib Disodium Hexahydrate
Fostamatinib disodium
R935788
CAS号
1025687-58-4
914295-16-2
PubChem SID
162037820
PubChem CID
25008120

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
PubChem 25008120 external link

理论计算性质

理论计算性质

JChem
Acid pKa 1.6923226  质子受体 13 
质子供体 LogD (pH = 5.5) 0.3786653 
LogD (pH = 7.4) -0.5220979  Log P 1.1271455 
摩尔折射率 134.8518 cm3 极化性 51.750275 Å3
极化表面积 192.38 Å2 可自由旋转的化学键 10 
里宾斯基五规则 false 

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
MSDS下载
下载链接 expand 查看数据来源
作用靶点
Syk expand 查看数据来源
成盐信息
sodium salt expand 查看数据来源
质检报告
下载链接 expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals TRC TRC
Selleck Chemicals -  S2206 external link
Biological Activity
Description R935788 (Fostamatinib disodium, R788) is a Syk inhibitor with IC50 of 41 nM.
Targets Syk
IC50 41 nM [1]
In Vitro R935788 is a methylene phosphate prodrug of R406, which can be rapidly converted to R406 in vivo. R406 (in vitro active form of R935788) selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells. [1] R406 inhibits cellular proliferation of a variety of diffuse large B-cell lymphoma (DLBCL) cell lines with EC50 values ranging from 0.8 μM to 8.1 μM. [2] R406 treatment reduces basal phosphorylation of BLNK, Akt, glycogen synthase kinase-3 (GSK-3), forkhead box O (FOXO) and ERK not only in cells with high (TCL-002) but also in cells with low levels of phosphorylated Syk (TCL1-551). In addition, R406 completely inhibits the anti-IgM induced Bcr signal in TCL1 leukemias. Despite the higher levels of constitutively active Syk in TCL1 leukemias, R406 is not selectively cytotoxic to the leukemic cells. [3]
In Vivo Given that plasma half-life of R406 in mice is less than 2 hours, R935788 is administered in 3 divided doses at 3-hour intervals to provide continuous Syk inhibition during each day of treatment, mimicking the longer plasma half-life in humans (15 hours). Despite the relatively modest cytotoxic effect in vitro, R935788 significantly inhibits the proliferation and survival of leukemic cell in vivo, which is associated with the blocking of antigen-dependent B-cell receptor (Bcr) signaling rather than inhibition of constitutive Syk activity. R935788 treatment at 80 mg/kg/day for 18-21 days potently inhibits tumor growth of TCL1-002, TCL1-551 and TCL1-870 in mice with undetectable leukemic CD5+/B220+ cells at the last day of treatment, significantly prolongs the survival of the treated mice with median survival increased from 45/46 days to 170/172 days, and completely eradicates the malignant cells in a substantial proportion of mice after a 6-month follow-up period without affecting the production of normal B lymphocytes. R935788 treatment also induces an early and transient migration of both normal and malignant B cells from spleen and lymph nodes to peripheral blood, which is subsequently followed by selective growth inhibition of the malignant B-cell population. In addition, R935788 is also effective against spontaneously developing TCL1 leukemias in Eμ-TCL1 transgenic mice. [3]
Clinical Trials A Phase II study of R935788 in advanced colorectal, non-small cell lung, head and neck, hepatocelluar and renal cell carcinomas and pheochromocytoma and thyroid tumors has been completed.
Features Clinically used oral formulation of R406
Protocol
Kinase Assay [1]
In vitro fluorescence polarization kinase assays R406 (in vitro active form of R935788) is serially diluted in DMSO and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated BGG). ATP and substrate in kinase buffer are added at room temperature, resulting in a final DMSO concentration on 0.2%. The kinase reactions are performed in a final volume of 20 μL containing 5 μM HS1 peptide substrate and 4 μM ATP and started by addition of 0.125 ng of Syk in kinase buffer. The reaction is allowed to proceed for 40 minutes at room temperature. The reaction is stopped by the addition of 20 μL of PTK quench mix containing EDTA/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptide tracer (0.5× final) diluted in FP Dilution Buffer. The plate is incubated for 30 minutes in the dark at room temperature and then read on a Polarion fluorescence polarization plate reader. Data is converted to determine the amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit. For IC50 determination, R406 is tested at eleven concentrations in duplicate and curve-fitting is performed by non-linear regression analysis using Prism GraphPad Software.
Cell Assay [2]
Cell Lines TCL1-002, TCL1-252, TCL1-551, TCL1-870, and TCL1-540
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 48 hours
Methods Cells are exposed to increasing concentrations of R406 (in vitro active form of R935788) for 48 hours. The percentage of apoptotic cells is determined by double staining with propidium iodide (PI) and annexin-A5–FITC conjugate. Ki-67 staining is performed with the FITC mouse anti–Ki-67 set. Samples are analyzed on a FACSCalibur flow cytometer with CellQuest Version 3.3 software.
Animal Study [2]
Animal Models B6/C3H F1 female mice intraperitoneally injected with TCL1-002, TCL1-551, or TCL1-870 leukemia cells, and Eμ-TCL1 transgenic mice
Formulation Formulated as a 4 mg/mL solution in 0.1% carboxymethylcellulose sodium, 0.1% methylparaben, and 0.02% propylparaben (pH 6.5)
Doses 80 mg/kg/day
Administration Intraperitoneal administration in 3 divided doses at 3-hour intervals
References
[1] Braselmann S, et al. J Pharmacol Exp Ther, 2006, 319(3), 998-1008.
[2] Chen L, et al. Blood, 2008, 111(4), 2230-2237.
[3] Suljagic M, et al. Blood, 2010, 116(23), 4894-4905.
Toronto Research Chemicals -  F745500 external link
A spleen tyrosine kinase inhibitor prodrug for the treatment of inflammatory diseases. An anti-inflammatory agent.

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参考文献

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