IC50: 0.014 and 0.48 μM for p38α and p38β enzymatic activity, respectively.
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].
Clinical trial: Up to now, pamapimod is still in the preclinical development stage.
Reference:
[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).