2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

• ChemBase编号: 72848
• 分子式: C16H17FIN3O4
• 平均质量: 461.2267532
• 单一同位素质量: 461.02478226
• SMILES: c1c(ccc(c1F)Nc1n(c(=O)c(cc1C(=O)NOCCO)C)C)I
• Canonical SMILES: OCCONC(=O)c1cc(C)c(=O)n(c1Nc1ccc(cc1F)I)C
• InChI: InChI=1S/C16H17FIN3O4/c1-9-7-11(15(23)20-25-6-5-22)14(21(2)16(9)24)19-13-4-3-10(18)8-12(13)17/h3-4,7-8,19,22H,5-6H2,1-2H3,(H,20,23)
• InChIKey: RWEVIPRMPFNTLO-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide
• IUPAC传统名: 2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide
• 别名: ARRY-424704; ARRY-704; AZD-8330; AZD8330

登记号

• CAS号: 869357-68-6
• PubChem SID: 162037769
• PubChem CID: 16666708

理论计算性质

• Acid pKa: 8.2902775
• 质子受体: 5
• 质子供体: 3
• LogD (pH = 5.5): 1.5901834
• LogD (pH = 7.4): 1.5445412
• Log P: 1.5908066
• 摩尔折射率: 110.5076 cm^3
• 极化性: 37.488205 Å^3
• 极化表面积: 90.9 Å^2
• 可自由旋转的化学键: 6
• 里宾斯基五规则: true

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: MEK

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2134

Research Area

• Description: Cancer

Biological Activity

• Description: AZD8330 (ARRY-424704) is a MEK 1/2 inhibitor with IC50 of 7 nM.
• Targets: MEK 1/2; ERK phosphorylation
• IC50: 7 nM; 0.4 nM ^[1]
• In Vitro: AZD8330 potently and strongly inhibits MEK 1/2. AZD8330 has no inhibitory activity against over 200 other kinases including at concentrations up to 10 μM. AZD8330 demonstrates sub-nanomolar potency in mechanistic (pERK) and low to sub-nanomolar potency in functional (proliferation) assays in MEK 1/2 inhibitor sensitive cell lines. ^[1]
• In Vivo: In a Calu-6 rat xenograft pharmacokinetic/pharmacodynamic (PK/PD) model a single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by > 90% for between 4 and 8 hours. Doses as low as 0.4 mg/kg once daily are sufficient for > 80% tumor growth inhibition in the Calu-6 nude rat xenograft model. In the Calu-6 model, AZD8330 inhibits tumor growth in a dose-dependent fashion, at 0.3 mg/kg and 1.0 mg/kg once daily. ^[1]
• Clinical Trials: A Phase I clinical trial for AZD8330 has been completed in the treatment of cancer.

Protocol

• Protocol: Kinase Assay ^[2]
• MEK1 enzymatic assays: NH2-terminal hexahistidine tagged, constitutively active MEK1 (S218D, S222D ΔR4F) is expressed in baculovirus-infected Hi5 insect cells and purified by immobilized metal affinity chromatography, ion exchange, and gel filtration. The activity of MEK1 is assessed by measuring the incorporation of [γ- ^33P]phosphate from [γ-^33P]ATP onto ERK2. The assay is carried out in a 96-well polypropylene plate with an incubation mixture (100 μL) composed of 25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM sodium orthovanadate, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, and 0 to 80 nM AZD8330 (final concentration of 1% DMSO). The reactions are initiated by the addition of 10 μM ATP (with 0.5 μC k[γ-^33P]ATP/well) and incubated at room temperature for 45 min. An equal volume of 25% trichloracetic acid is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filter plates, excess labeled ATP is washed off with 0.5% phosphoric acid, and radioactivity is counted in a liquid scintillation counter. ATP dependence is determined by varying the amount of ATP in the reaction mixture. The data are globally fitted.
• Protocol: Cell Assay ^[1]
• Cell Lines: Malme-3M melanoma cells
• Concentrations: ~10 μM
• Incubation Time: 1 hour
• Methods: Malme-3M melanoma cells are plated in 96-wells and treated with various concentrations of AZD8330 for 1 hour at 37 °C. The cells are fixed, permeabilized, and incubated with an anti-phospho-ERK antibody and an anti-ERK 1/2 antibody. Plates are washed and fluorescently-labeled secondary antibodies are added. Plates are analyzed on a LICOR fluorescence imager. The pERK signal is normalized to the total ERK signal.
• Protocol: Animal Study ^[1]
• Animal Models: Female nude rats (NIH rnu/rnu) with Calu-6 cells, nude rats with SW620 cells
• Formulation: 0.5% HPMC-0.1% Tween
• Doses: 0.3 mg/kg, 1 mg/kg
• Administration: Oral administration

References

• References: [1] Wallace EM, et al. AACR Annual Meeting, 2009, Abst 3696.
• References: [2] Yeh TC, et al. Clin Cancer Res, 2007, 13(5), 1576-1583.

参考文献

• Wallace EM, et al. AACR Annual Meeting, 2009, Abst 3696.
• Yeh TC, et al. Clin Cancer Res, 2007, 13(5), 1576-1583.