Uses
A selective inhibitor of the α-isoform of p38 MAP kinase
Definition
ChEBI: A member of the class of pyridopyrimidines that is 8-methylpyrido[2,3-d]pyrimidin-7(8H)-one carrying additional (1,5-dihydroxypentan-3-yl)amino and 2,4-difluorophenoxy substituents at positions 2 and 6 respectively. It is a
otent inhibitor of MAPK and is used for treatment of rheumatoid arthritis.
Biological Activity
pamapimod (r-1503, ro4402257) is a p38 mapk inhibitor.p38alpha, a protein kinase, regulates the inflammatory cytokine expression, indicating a key role in the pathogenesis of diseases such as rheumatoid arthritis and systemic lupus erythematosus.
in vitro
pamapimod could inhibit p38alpha and p38beta enzymatic activity, and there was no activity against p38delta or p38gamma. when profiled across 350 kinases, pamapimod bound only to four kinases. moreover, pamapimod was found to inhibit p38, but jnk inhibition was not detected. pamapimod also inhibited lps-stimulated tnfα production by monocytes, il-1β production. in addition, lps- and tnfα-stimulated production of tnfα and il-6 in rodent plasma could be also inhibited by pamapimod [1].
in vivo
in murine collagen-induced arthritis, pamapimod was able to reduce the clinical signs of inflammation and bone loss at 50 mg/kg or greater. moreover, pamapimod dose-dependently increased the tolerance pressure in a rat model of hyperalgesia, indicating the critical role of p38 in pain associated with inflammation. furthermore, a pamapimod analog had equivalent potency and selectivity in lupus-prone mrl/lpr mice [1].
IC 50
0.014 and 0.48 μm for p38α and p38β enzymatic activity, respectively.
References
[1] hill, r. j. et al. pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. the journal of pharmacology and experimental therapeutics 327, 610-619, doi:10.1124/jpet.108.139006 (2008).
