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869357-68-6 molecular structure
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2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

ChemBase ID: 72848
Molecular Formular: C16H17FIN3O4
Molecular Mass: 461.2267532
Monoisotopic Mass: 461.02478226
SMILES and InChIs

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

Cite this record

CBID:72848 http://www.chembase.cn/molecule-72848.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide
IUPAC Traditional name
2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide
Synonyms
ARRY-424704
ARRY-704
AZD-8330
AZD8330
CAS Number
869357-68-6
PubChem SID
162037769
PubChem CID
16666708

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S2134 external link Add to cart Please log in.
Data Source Data ID
PubChem 16666708 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 8.2902775  H Acceptors
H Donor LogD (pH = 5.5) 1.5901834 
LogD (pH = 7.4) 1.5445412  Log P 1.5908066 
Molar Refractivity 110.5076 cm3 Polarizability 37.488205 Å3
Polar Surface Area 90.9 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Target
MEK expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S2134 external link
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.
Features
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.
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.
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
[1] Wallace EM, et al. AACR Annual Meeting, 2009, Abst 3696.
[2] Yeh TC, et al. Clin Cancer Res, 2007, 13(5), 1576-1583.

REFERENCES

REFERENCES

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PATENTS

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