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PH-797804

Name: PH-797804
Brand: Selleck Chemicals
SKU: S2726
Rating: 5 (32 reviews)

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.

CAS No. 586379-66-0

Selleck's PH-797804 has been cited by 32 publications

Purity & Quality Control

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p38 MAPK Signaling Pathway Map

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	Mn3ISpVv[3Srb36gZZN{[Xl?	NFHkS2ZKdmirYnn0bY9vKG:oIICzPIFteGijIHvpcoF{\S2mZYDlcoRmdnRiSGPQMVI4KHCqb4PwbI9zgWyjdHnvckBqdiCqdX3hckBWQTN5IHPlcIx{NCCLQ{WwQVAvODBzMEWg{txO	NUfDe4Z7OjF4MkC2PVk>
human monocytes	M2nXeGZ2dmO2aX;uJIF{e2G7	NWWx[GFvSW62aXnu[oxidW2jdH;yfUBi[3Srdnn0fUBqdiCqdX3hckBud26xY4n0[ZMh[XO\|ZYPz[YQh[XNiaX7obYJqfGmxbjDv[kBNWFNvaX7keYNm\CCWTl\hcJBp[SCycn;keYN1cW:wLDDJR\|UxRTBwMECzOEDPxE1?	MkHYNlE3OjB4OUm=
human PBMC	NHjFRZZHfW6ldHnvckBie3OjeR?=	NFj1UmlCdnSraX7mcIFudWG2b4L5JIFkfGm4aYT5JIlvKGi3bXHuJHBDVUNiYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iCOUGOtbY5lfWOnZDDUUmZidHCqYTDy[Yxm[XOnIIDy[ZRz\WG2ZXSg[o9zKDFiaIKgZoVnd3KnIFzQV{B1emWjdH3lcpQhdWWjc4Xy[YQh[W[2ZYKgNVghcHK\|LDDJR\|UxRTBwMEG1JO69VQ>?	M33MWlIyPjRzMkGx

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.
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

References

Solubility (25°C)

In vitro


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. Click to purchase: PEG300 Tween 80	5mg/mL

Chemical Information

Molecular Weight	477.3
Formula	C₂₂H₁₉BrF₂N₂O₃
CAS No.	586379-66-0
Storage	3 years	-20°C	powder
Storage	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

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In vivo Formulation Calculator (Clear solution)

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

Dosage: mg/kg Average weight of animals: g Dosing volume per animal:μL Number of animals:

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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
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Molarity Calculator

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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)

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