Home MAPK p38 MAPK inhibitor PH-797804

PH-797804

Catalog No.S2726

For research use only.

PH-797804 is a novel pyridinone inhibitor of p38α with IC50 of 26 nM in a cell-free assay; 4-fold more selective versus p38β and does not inhibit JNK2. Phase 2.

PH-797804 Chemical Structure

CAS No. 586379-66-0

Selleck's PH-797804 has been cited by 31 publications

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p38 MAPK Signaling Pathways

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Biological Activity

Description PH-797804 is a novel pyridinone inhibitor of p38α with IC50 of 26 nM in a cell-free assay; 4-fold more selective versus p38β and does not inhibit JNK2. Phase 2.
Targets
p38α [1]
(Cell-free assay)		 p38β [1]
(Cell-free assay)
26 nM 102 nM
In 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. 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. [1] 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. [2]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human U937 cells M2nMfmZ2dmO2aX;uJIF{e2G7 M3PXRWlvcGmkaYTpc44hd2ZicEO4ZYxxcGFia3nuZZNmNWSncHXu[IVvfCCKU2CtNlcheGixc4Doc5J6dGG2aX;uJIlvKGi3bXHuJHU6OzdiY3XscJMtKEmFNUC9NE4xODFyNTFOwG0> MojJNlE3OjB4OUm=
human monocytes MmXtSpVv[3Srb36gZZN{[Xl? M17kRmFvfGmrbn\sZY1u[XSxcomgZYN1cX[rdImgbY4hcHWvYX6gcY9vd2O7dHXzJIF{e2W|c3XkJIF{KGmwaHnibZRqd25ib3[gUHBUNWmwZIXj[YQhXE6IYXzwbIEheHKxZIXjeIlwdixiSVO1NF0xNjByM{Sg{txO M3jIbFIyPjJyNkm5
human PBMC M3rIbGZ2dmO2aX;uJIF{e2G7 NYDwXmlRSW62aXnu[oxidW2jdH;yfUBi[3Srdnn0fUBqdiCqdX3hckBRSk2FIHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiTGDTMYlv\HWlZXSgWG5H[WyyaHGgdoVt\WG|ZTDwdoV1emWjdHXkJIZweiBzIHjyJIJm\m:{ZTDMVHMhfHKnYYTt[Y51KG2nYYP1doVlKGGodHXyJFE5KGi{czygTWM2OD1yLkCxOUDPxE1? M3fmTFIyPjRzMkGx
Click to View More Cell Line Experimental Data
In vivo Orally 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. [1]

Protocol (from reference)

Kinase Assay:

[1]
  • P38 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 Research:

[1]
  • Cell lines: Rheumatoid arthritis synovial fibroblast(s)
  • Concentrations: --
  • Incubation Time: --
  • Method:

    Cell viability is evaluated using the 3-(4,5-dimethylthiazol-2-yl)-) diphenyl tetrazolium bromide assay. Absorbance is measured on an ELISA plate reader with a test wavelength of 570 nm and a reference of 630 nm.

  • (Only for Reference)
Animal Research:

[1]
  • Animal Models: LPS-induced chronic inflammation rat model
  • Dosages: 0.001-1 mg/kg
  • Administration: Oral gavage 4 hours before LPS administration
  • (Only for Reference)

Solubility (25°C)

In vitro

 DMSO 96 mg/mL
(201.13 mM)
Ethanol 7 mg/mL
(14.66 mM)
Water Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.

 5mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 477.3
Formula

C22H19BrF2N2O3
CAS No. 586379-66-0
Storage 3 years -20°C powder
2 years -80°C in solvent
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

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

mg/kg g μL

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

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Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01217918 Completed Drug: 1 mg|Drug: 5 mg|Drug: 10 mg Healthy Pfizer October 2010 Phase 1
NCT00827515 Withdrawn Drug: PH797804 Pain Pfizer February 2009 Phase 1
NCT00614705 Completed Drug: PH-797804|Drug: Placebo Neuralgia Postherpetic Pfizer April 2008 Phase 2
NCT00620685 Completed Drug: Placebo|Drug: PH-797804 Arthritis Rheumatoid Pfizer March 2008 Phase 2

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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