Abstract
P38α is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38α and p38β enzymatic activity, with IC50 values of 0.014 ± 0.002 and 0.48 ± 0.04 μM, respectively. There was no activity against p38δ or p38γ isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH2-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC50, 0.06 μM), but inhibition of 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 RA patients. 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. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38α with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.139006.
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ABBREVIATIONS: RA, rheumatoid arthritis; MAPK, mitogen-activated protein kinase; TNF, tumor necrosis factor; IL, interleukin; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SB202190, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole; LPS, lipopolysaccharide; ELISA, enzyme-linked immunosorbent assay; JNK, c-Jun NH2-terminal kinase; HSP, heat shock protein; TBST, Tris-buffered saline/Tween 20; CT, computerized tomography; HWB, human whole blood; MAPKAPK, mitogen-activated protein kinase-activated protein kinase.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received March 14, 2008.
- Accepted September 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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