PH-797804

Alias: PH 797804; PH797804; PH-797804
Cat No.:V0481 Purity: ≥98%
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.
PH-797804 Chemical Structure CAS No.: 586379-66-0
Product category: p38 MAPK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product 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. In a cell-free assay, it inhibits p38α with an IC50 of 26 nM, demonstrates a 4-fold preference for p38α over p38β, and has no effects on JNK2. Excellent anti-proliferative activity against colon tumor cells and high in vivo antitumor efficacy are both displayed by PH-797804 in three PDXs. It might be helpful in the treatment of colon cancer and rheumatoid arthritis.
Biological Activity I Assay Protocols (From Reference)
Targets
p38α (IC50 = 26 nM); p38α (Ki = 5.8 nM); p38β (Ki = 40 nM)
ln Vitro
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. At concentrations up to 1 μM, PH-797804 has no inhibitory impact on the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells. With an IC50 of 3 nM in primary rat bone marrow cells, PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner.[1] The activity of PH-797804 is specific because the IC50 values for it against the following targets have been found to be higher than 200 μM (unless otherwise noted): CDK2, ERK2, IKK1, IKK2, IKKi, MAPKAP2, MAPKAP3, MKK7 (>100 μM), MNK, MSK (>164 μM), PRAK, RSK2, and TBK1.[2]
ln Vivo
In both rats and cynomolgus monkeys, oral administration of PH-797804 effectively reduces the acute inflammatory reactions brought on by systemically administered endotoxin. In chronic disease models, PH-797804 treatment for 10 days shows strong anti-inflammatory activity, significantly lowering joint inflammation and related bone loss in rats with streptococcal cell wall-induced arthritis and mice with collagen-induced arthritis. In rats and cynomolgus monkeys, the ED50 values were 0.07 mg/kg and 0.095 mg/kg, respectively, according to dose-response analysis. In a human endotoxin challenge model, PH-797804 inhibits LPS-induced TNF-α, IL-6, and MK-2 activity in a dose- and concentration-dependent manner.[1]
Enzyme Assay
The phosphorylation of GST-c-Jun or the epidermal growth factor receptor peptide (EGFRP) by p38 kinases is assessed using a resin capture assay method. 25 mM HEPES, pH 7.5, 10 mM magnesium acetate, 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 p38 kinase reactions are included in reaction mixtures. To begin the reaction, 25 nM p38α kinase is added, resulting in a final volume of 50 μl. For 30 minutes, the p38α kinase reactions are incubated at 25 °C. Under these circumstances, both p38 kinase's product formation is time-dependently linear. The addition of 150 μl of AG 1 × 8 ion exchange resin in 900 mM sodium formate, pH 3.0, stops the reaction and removes the unreacted [γ-33P]ATP. Solutions are thoroughly combined and then left to stand for 5 minutes. The phosphorylated substrate is extracted from the mixture in a 50-μl aliquot, which is then transferred to a 96-well plate. A TopCount NXT microplate scintillation and luminescence counter is used to add 150 μL of the MicroScint-40 scintillation cocktail to each well and measure the radioactivity levels.
Cell Assay
The 3-(4,5-dimethylthiazol-2-yl)-) diphenyl tetrazolium bromide assay is used to measure cell viability. With a reference wavelength of 630 nm and a test wavelength of 570 nm, absorbance is measured on an ELISA plate reader.
Animal Protocol
LPS-induced chronic inflammation rat model
0.001-1 mg/kg
Oral gavage 4 hours before LPS administration
References

[1]. J Pharmacol Exp Ther . 2009 Dec;331(3):882-95.

[2]. Biochemistry . 2009 Jul 14;48(27):6402-11.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H19BRF2N2O3
Molecular Weight
477.3
Exact Mass
477.300
Elemental Analysis
C, 55.36; H, 4.01; Br, 16.74; F, 7.96; N, 5.87; O, 10.06
CAS #
586379-66-0
Appearance
Solid powder
SMILES
CC1=C(C=C(C=C1)C(=O)NC)N2C(=CC(=C(C2=O)Br)OCC3=C(C=C(C=C3)F)F)C
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)
Chemical Name
3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-N,4-dimethylbenzamide
Synonyms
PH 797804; PH797804; PH-797804
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
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
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.0951 mL 10.4756 mL 20.9512 mL
5 mM 0.4190 mL 2.0951 mL 4.1902 mL
10 mM 0.2095 mL 1.0476 mL 2.0951 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00383188 Completed Drug: placebo
Drug: PH-797804
Arthritis, Rheumatoid Pfizer December 15, 2006 Phase 2
NCT01102660 Completed Drug: PH-797804
Drug: Placebo
Osteoarthritis Pfizer May 2010 Phase 2
NCT01479647 Completed Drug: PH-797804 Healthy Volunteers Pfizer December 2011 Phase 1
NCT01217918 Completed Drug: 1 mg
Drug: 5 mg
Healthy Pfizer October 2010 Phase 1
NCT02084485 Completed Drug: PH-797804
Drug: Placebo
Healthy Pfizer September 2006 Phase 1
Biological Data
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