pamapimod has been researched along with Osteoporosis* in 2 studies
2 other study(ies) available for pamapimod and Osteoporosis
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The Novel p38 Inhibitor, Pamapimod, Inhibits Osteoclastogenesis and Counteracts Estrogen-Dependent Bone Loss in Mice.
Pamapimod (PAM) is a novel selective p38 mitogen-activated protein (MAP) kinase inhibitor proved to be effective in rheumatoid arthritis in phase 2 clinical trial. However, its effect on osteoclast-associated osteoporosis and the underlying mechanisms remain unclear. In this study, we showed that PAM suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation via inhibition of p38 phosphorylation and subsequent c-Fos and nuclear factor of activated T cells c1 (NFATc1) expression. In addition, the downregulated NFATc1 leads to reduced expression of its targeting gene disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), which was further proven to be critical for osteoclastic bone resorption. Therefore, we treated ovariectomized (OVX) mice with PAM and revealed a protective effect of PAM on osteoporosis in vivo. In conclusion, our results demonstrated PAM can prevent OVX-induced bone loss through suppression of p38/NFATc1-induced osteoclast formation and NFATc1/ADAM12-associated bone resorption. © 2018 American Society for Bone and Mineral Research. Topics: ADAM12 Protein; Animals; Enzyme Inhibitors; Estrogens; Female; Mice; NFATC Transcription Factors; Osteoclasts; Osteoporosis; Ovariectomy; p38 Mitogen-Activated Protein Kinases; Pyridones; Pyrimidines | 2019 |
Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity.
P38alpha 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 p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. There was no activity against p38delta or p38gamma 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 NH(2)-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC(50), 0.06 microM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha production by monocytes, interleukin (IL)-1beta production in human whole blood, and spontaneous TNFalpha production by synovial explants from RA patients. LPS- and TNFalpha-stimulated production of TNFalpha 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 p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases. Topics: Animals; Arthritis, Rheumatoid; Drug Evaluation, Preclinical; Humans; Inflammation; Inhibitory Concentration 50; Interleukin-1beta; Interleukin-6; Kidney Diseases; Mice; Monocytes; Osteoporosis; p38 Mitogen-Activated Protein Kinases; Protein Isoforms; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Synovial Fluid; Treatment Outcome; Tumor Necrosis Factor-alpha | 2008 |