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Pamapimod is a novel p38 mitogen-activated protein kinase inhibitor, inhibited p38alpha and p38beta enzymatic activity, with IC50 values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) α production by monocytes, interleukin (IL)-1β production in human whole blood, and spontaneous TNFα production by synovial explants from RA patients. LPS- and TNFα-stimulated production of TNFα and IL-6 in rodents also was inhibited by pamapimod.
In vivo: In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation.
| Cell Experiment | |
|---|---|
| Cell lines | Human Monocytic Cell Line, THP-1 |
| Preparation method | THP-1 cells, growing in log phase, were collected by centrifugation and resuspended in RPMI 1640 containing 5.5×10-5 M 2-mercaptoethanol and 10% fetal bovine serum to a final cell concentration of 2.5×106 cells/ml. Dilutions of pamapimod were predispensed in 25 μl aliquots (before addition of cells) into round-bottom 96-well plates. The starting concentration was 100 μM in 5% dimethyl sulfoxide, and six half-log serial dilutions were made. After the addition of 200 μl of cell suspension and 25 μl of 5 μg/ml LPS in medium, the final dimethyl sulfoxide concentration was 0.5%. Compounds were diluted an additional 10-fold, and the final LPS concentration was 500 ng/ml. The cell suspensions and compound dilutions were combined and incubated for 30 min at 37°C in a 5% CO2 humidified atmosphere, before the addition of LPS (or medium for non-LPS control samples). After the addition of LPS, plates were incubated for 2 h, followed by centrifugation to pellet cells. Cell supernatants were stored at 4°C until analysis for TNF-α content. TNF-α levels were determined by ELISA. Cytokine concentrations were determined. |
| Concentrations | 15 μM |
| Incubation time | 150 min |
| Animal Experiment | |
|---|---|
| Animal models | BALB/c mice |
| Formulation | 0.9% NaCl, 0.5% sodium carboxymethylcellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol, and 97.3% distilled water. |
| Dosages | 25, 50, 100, 150 mg/kg |
| Administration | oral administration |
| Molecular Weight | 406.38 |
| Formula | C19H20F2N4O4 |
| CAS Number | 449811-01-2 |
| Solubility (25°C) | DMSO 80 mg/mL Ethanol 20 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related p38 MAPK Products |
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SSK1 is a senescence-specific killing compound and is a precursor for β-galactosidase, which can reduce the inflammatory response. SSK1 can activate the phosphorylation of p38 MAPK and MKK3/MKK6 in senescent cells, promote mitochondrial DNA damage and selectively killed senescent cells. |
| p38 MAP Kinase Inhibitor III
p38 MAP Kinase Inhibitor III is a p38 MAPK inhibitor with an IC50 of 0.9 μM. p38 MAP Kinase Inhibitor III also inhibits IL-1β and TNF-α release with IC50 values of 0.37 μM and 0.044 μM, respectively. |
| (R)-STU104
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| SB 706504
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| RWJ-67657
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