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PH-797804 586379-66-0

Product Description

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Molecular Weight:

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


Biological 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.


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.


Protocol(Only for 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 Assay: [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 Study: [1]

Animal Models LPS-induced chronic inflammation rat model
Formulation PH-797804 is prepared as a suspension in a vehicle consisting of 0.5% methylcellulose and 0.025% Tween 20.
Dosages 0.001-1 mg/kg
Administration Oral gavage 4 hours before LPS administration
Solubility 0.5% methylcellulose/0.2% Tween 80, 30 mg/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.


Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)


Species Baboon Dog Monkey Rabbit Guinea pig Rat Hamster Mouse
Weight (kg) 12 10 3 1.8 0.4 0.15 0.08 0.02
Body Surface Area (m2) 0.6 0.5 0.24 0.15 0.05 0.025 0.02 0.007
Km factor 20 20 12 12 8 6 5 3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by Animal B Km
Animal A Km



For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × mouse Km(3) = 11.2 mg/kg
rat Km(6)









Chemical Information




Molecular Weight (MW) 477.3
Formula

C22H19BrF2N2O3

CAS No. 586379-66-0

Storage 3 years -20℃Powder
6 months-80℃in solvent (DMSO, water, etc.)
Synonyms



Solubility (25°C) * In vitro DMSO 96 mg/mL (201.13 mM)
Water <1 mg/mL (
Ethanol 7 mg/mL (14.66 mM)
In vivo 0.5% methylcellulose/0.2% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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 Name 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide







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