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    PH-797804
    PH-797804

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0481
    CAS #: 586379-66-0Purity ≥98%

    Description: PH-797804 (PH797804), a diarylpyridinone analog, is a novel, potent, selective and ATP-competitive inhibitor of p38 mitogen-activated protein (p38α) with potential anti-inflammatory and anticancer activity. It inhibits p38α with an IC50 of 26 nM in a cell-free assay, and shows 4-fold higher selectivity for p38α over p38β andhas no effects on JNK2. PH-797804 exhibits excellent anti-proliferative activity against colon tumor cells and high in vivo antitumor efficacy in three PDXs. It may have usefulness in the treatment of arthritis and colon cancer. 

    References: J Pharmacol Exp Ther. 2009 Dec;331(3):882-95; Biochemistry. 2009 Jul 14;48(27):6402-11.

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    Molecular Weight (MW)477.3
    FormulaC22H19BrF2N2O3
    CAS No.586379-66-0
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 96 mg/mL (201.1 mM)
    Water: <1 mg/mL
    Ethanol: 7 mg/mL (14.7mM)
    Solubility (In vivo)2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5mg/mL
    Synonyms

    Synonym: PH 797804; PH797804; PH-797804.

    Chemical Name: 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide

    InChi Key: KCAJXIDMCNPGHZ-UHFFFAOYSA-N

    InChi Code: InChI=1S/C22H19BrF2N2O3/c1-12-4-5-14(21(28)26-3)9-18(12)27-13(2)8-19(20(23)22(27)29)30-11-15-6-7-16(24)10-17(15)25/h4-10H,11H2,1-3H3,(H,26,28)

    SMILES Code: O=C(NC)C1=CC=C(C)C(N2C(C)=CC(OCC3=CC=C(F)C=C3F)=C(Br)C2=O)=C1


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    In Vitro

    In vitro activity: PH-797804 blocks LPS-induced TNF-α production and p38 kinase activity in the human monocytic U937 cell line, with comparable IC50 of 5.9 nM and 1.1 nM. PH-797804 has no inhibitory effect on either the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells at concentrations up to 1 μM. PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner, with IC50 of 3 nM in primary rat bone marrow cells. IC50 values for PH-797804 against the following targets have been determined to be greater than 200 μM (unless specified): CDK2, ERK2, IKK1, IKK2, IKKi, MAPKAP2, MAPKAP3, MKK7 (>100 μM), MNK, MSK (>164 μM), PRAK, RSK2, and TBK1, which means the activity of PH-797804 is specific.


    Kinase Assay: A resin capture assay method is used to determine the phosphorylation of epidermal growth factor receptor peptide (EGFRP) or GST-c-Jun by p38 kinases. Reactions mixtures contain 25 mM HEPES, pH 7.5, 10 mM magnesium acetate, ATP (at the indicated concentration), 0.05 to 0.3 μCi of [γ-33P]ATP, 0.8 mM dithiothreitol, and either 200 μM EGFRP or 10 μM GST-c-Jun for p38α kinase reactions. The reaction is initiated by the addition of 25 nM p38α kinase to give a final volume of 50 μl. The p38αkinase reactions are incubated at 25 °C for 30 minutes. Under these conditions, the formation of product for both p38αkinase is linear with time. The reaction is stopped, and the unreacted [γ-33P]ATP is removed by the addition of 150 μl of AG 1 × 8 ion exchange resin in 900 mM sodium formate, pH 3.0. Once thoroughly mixed, solutions are allowed to stand for 5 minutes. A 50-μl aliquot of head volume containing the phosphorylated substrate is removed from the mixture and transferred to a 96-well plate. MicroScint-40 scintillation cocktail (150 μL) is added to each well and the radioactivity quantities using a TopCount NXT microplate scintillation and luminescence counter. 


    Cell Assay: PH-797804 blocks LPS-induced TNF-α production and p38 kinase activity in the human monocytic U937 cell line, with comparable IC50 of 5.9 nM and 1.1 nM. PH-797804 has no inhibitory effect on either the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells at concentrations up to 1 μM. PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner, with IC50 of 3 nM in primary rat bone marrow cells

    In VivoOrally dosing of PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. PH-797804 treatment for 10 days demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Dose-response analysis resulted in ED50 values of 0.07 mg/kg and 0.095 mg/kg in rat and cynomolgus monkeys, respectively. PH-797804 inhibits LPS-induced TNF-α, IL-6, and MK-2 activity in a dose- and concentration-dependent manner in a human endotoxin challenge model.
    Animal modelLPS-induced chronic inflammation rat model
    Formulation & DosageDissolved in a vehicle consisting of 0.5% methylcellulose and 0.025% Tween 20; 0.001-1 mg/kg; p.o.
    References

    J Pharmacol Exp Ther. 2009 Dec;331(3):882-95; Biochemistry. 2009 Jul 14;48(27):6402-11.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    PH-797804

    PH-797804
    PH-797804


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