Pamapimod is a selective inhibitor of p38 mitogen-activated protein kinase. It inhibits p38α and p38β enzymatic activity with IC50 values of 0.014±0.002 and 0.48± 0.04 mM, respectively with no activity against p38delta or p38gamma isoforms.
The family members of the mitogen-activated protein kinase (MAPK) mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes[3]. Pamapimod inhibited p38α and p38β enzymatic activity, with IC50 values of 0.014 ± 0.002 and 0.48 ± 0.04 μM, respectively[4]. Pamapimod inhibited p38 (IC50, 0.06 μM), but inhibition of c-Jun NH(2)-terminal kinase (JNK) was not detected. 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 rheumatoid arthritis (RA) patients[4]. Intravenous systemic clearance of pamapimod was low to moderate across species pamapimod was well absorbed and had high oral bioavailability in the rat, monkey, and dog (62%-80%)[5]. LPS- and TNFα-stimulated production of TNFα and IL-6 in rodents also was inhibited by pamapimod. 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[4]. we treated ovariectomized (OVX) mice with pamapimod and revealed a protective effect of pamapimod on osteoporosis in vivo[6].
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