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]
Cell Assay: [1]
Animal Study: [1]
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
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.
Chemical Information
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Contact us if you need more details on 586379-66-0. We are ready to answer your questions on packaging, logistics, certification or any other aspects about PH-797804 586379-66-0、586379-66-0 PH-797804. If these products fail to match your need, please contact us and we would like to provide relevant information.
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. |
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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 |
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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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Molarity Calculator
Dilution Calculator
Molecular Weight Calculator
Contact us if you need more details on 586379-66-0. We are ready to answer your questions on packaging, logistics, certification or any other aspects about PH-797804 586379-66-0、586379-66-0 PH-797804. If these products fail to match your need, please contact us and we would like to provide relevant information.
Product Categories : MAPK > p38 MAPK Inhibitor
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