Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity

@article{Hill2008PamapimodAN,
  title={Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity},
  author={Ronald J. Hill and Karim Dabbagh and Deborah J. Phippard and Ching Li and Rebecca T. Suttmann and Mary Welch and Eva Werkne Papp and Kyung W. Song and Kung-ching Chang and David Leaffer and Yong-Nam Kim and Rick Roberts and Tanja S. Zabka and Dee Aud and Joseph M. Dal Porto and Anthony M. Manning and Stanford L. Peng and David Goldstein and Brian R. Wong},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2008},
  volume={327},
  pages={610 - 619}
}
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… 

Figures and Tables from this paper

Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders.
TLDR
It is concluded that p38R inhibition alone is unlikely to be a successful strategy toward treating chronic inflammatory disorders and the era of optimism surrounding the use of p38 MAPK inhibition for the treatment of RA is over.
Metabolism of a novel skepinone L-like p38 mitogen-activated protein kinase inhibitor
TLDR
The objective of the current study was the preclinical characterization of 3-((2,4-difluorophenyl)amino)dibenzo[b,e]oxepin-11(6H)-one, a potent p38α MAP kinase inhibitor, which is completely inactivated by a CYP2B6 mediated phase 1 metabolism.
Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species
TLDR
The data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans, and human tissues should be considered early in the drug development process of p38 MAPK inhibitors.
p38α mitogen-activated protein kinase inhibitors, a patent review (2005 – 2011)
TLDR
In the last few years, compounds have become more potent and more selective, for example, by induction of the so-called glycine flip, and some companies are striving for selectivity with respect to isoforms.
The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer
TLDR
The p38 MAPK plays an important role in key cellular processes related to inflammation and cancer, and understanding the signal transduction mechanisms and gene regulation by p38MAPK provides useful information in the development of p 38 MAPK inhibitors with therapeutic benefits with reduced side effects.
The Novel p38 Inhibitor, Pamapimod, Inhibits Osteoclastogenesis and Counteracts Estrogen‐Dependent Bone Loss in Mice
  • Xiangde Zhao, L. Ning, Shuanglin Wan
  • Biology, Medicine
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 2019
TLDR
It is demonstrated PAM can prevent OVX‐induced bone loss through suppression of p38/NFATc1‐induced osteoclast formation and NFATc 1/ADAM12‐associated bone resorption.
Evaluation of the therapeutic potential of the selective p38 MAPK inhibitor Skepinone-L and the dual p38/JNK 3 inhibitor LN 950 in experimental K/BxN serum transfer arthritis
TLDR
Both the selective p38 MAPK inhibitor Skepinone-L and the dual inhibitor LN 950 exhibited significant therapeutic effects during experimental arthritis, and contributes to the ongoing discussion on the use of p38MAPK as a potential target in RA.
Dibenzosuberones as p38 mitogen-activated protein kinase inhibitors with low ATP competitiveness and outstanding whole blood activity.
TLDR
An approach to the development of such inhibitors of p38α mitogen-activated protein (MAP) kinase on the basis of the highly selective molecular probe Skepinone-L is described, finding that introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds.
A meta-analysis of the role of p38 mitogen-activated protein kinase inhibitors in patients with active rheumatoid arthritis
TLDR
A meta-analysis of all published randomized controlled trials to evaluate the efficacy and safety of p38 MAPK inhibitors in patients with active RA showed that a better American College of Rheumatology 20 % improvement was observed in the p38 inhibitors group compared with the placebo group, but there were no meaningful differences in ACR50, Disease Activity Score in 28 joints response, and CRP levels.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 50 REFERENCES
Inflammation-activated protein kinases as targets for drug development.
  • M. Karin
  • Biology
    Proceedings of the American Thoracic Society
  • 2005
TLDR
Preliminary preclinical data suggest that inhibitors that target all these pathways exhibit antiinflammatory activity and the possible mechanisms through which such inhibitors may interfere with inflammation and some of the complications that may be associated with their use are focused on.
A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis
TLDR
In a model of experimental arthritis associated with significant osteolysis, p38α MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.
A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis.
TLDR
In a model of experimental arthritis associated with significant osteolysis, p38alpha MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.
Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis.
TLDR
Selective MKK3 deficiency can suppress inflammatory arthritis and cytokine production while Toll-like receptor 4-mediated host defense remains intact.
Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development.
TLDR
These results, in addition to proof of concept studies in rheumatoid patients, have established p38 inhibition as an avenue for the future management of pro-inflammatory cytokine based diseases.
p38 Mitogen-Activated Protein Kinase Contributes to Autoimmune Renal Injury in MRL-Faslpr Mice
TLDR
Evidence is provided that the regulation of p38 MAPK is a novel target for the therapy of renal injury in systemic lupus erythematosus and oral administration of FR167653 reduced the accumulation of macrophages and T cell and prevented kidney pathology, resulting in prolonged survival.
Generation and Characterization of p38β (MAPK11) Gene-Targeted Mice
TLDR
The generation and initial characterization of a knockout of the p38β (MAPK11) gene are reported, suggesting that p38α, and not p38 β, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p 38β during the development of p38 inhibitors.
R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models.
p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases
TLDR
An overview of the role of p 38 MAP kinases in stress-activated pathways and the progress towards clinical development of p38 MAP kinase inhibitors in the treatment of inflammatory diseases is provided.
p38 Mitogen-activated protein kinase contributes to autoimmune renal injury in MRL-Fas lpr mice.
TLDR
Evidence is provided that the regulation of p38 MAPK is a novel target for the therapy of renal injury in systemic lupus erythematosus and FR167653 reduced the accumulation of macrophages and T cell and prevented kidney pathology, resulting in prolonged survival.
...
1
2
3
4
5
...