The MAPK (mitogen-activated protein kinase) p38 is an important mediator of inflammation and of inflammatory and neuropathic pain. We have described recently that docking-groove-dependent interactions are important for p38 MAPK-mediated signal transduction. Thus virtual screening was performed to identify putative docking-groove-targeted p38 MAPK inhibitors. Several compounds of the benzo-oxadiazol family were identified with low micromolar inhibitory activity both in a p38 MAPK activity assay, and in THP-1 human monocytes acting as inhibitors of LPS (lipopolysaccharide)-induced TNFα (tumour necrosis factor α) secretion. Positions 2 and 5 in the phenyl ring are essential for the described inhibitory activity with a chloride in position 5 and a methyl group in position 2 yielding the best results, giving an IC50 value of 1.8 μM (FGA-19 compound). Notably, FGA-19 exerted a potent and long-lasting analgesic effect in vivo when tested in a mouse model of inflammatory hyperalgesia. A single intrathecal injection of FGA-19 completely resolved hyperalgesia, being 10-fold as potent and displaying longer lasting effects than the established p38 MAPK inhibitor SB239063. FGA-19 also reversed persistent pain in a model of post-inflammatory hyperalgesia in LysM (lysozyme M)-GRK2 (G-protein-coupled-receptor kinase)+/− mice. These potent in vivo effects suggested p38 MAPK docking-site-targeted inhibitors as a potential novel strategy for the treatment of inflammatory pain.
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Research Article|
April 11 2014
A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia
Hanneke L. D. M. Willemen;
Hanneke L. D. M. Willemen
1
*Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
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Pedro M. Campos;
†Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Madrid, Spain
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Elisa Lucas;
Elisa Lucas
†Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Madrid, Spain
‡Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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Antonio Morreale;
Antonio Morreale
3
§Centro de Biología Molecular “Severo Ochoa”, UAM-CSIC, Madrid, Spain
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Rubén Gil-Redondo;
Rubén Gil-Redondo
4
§Centro de Biología Molecular “Severo Ochoa”, UAM-CSIC, Madrid, Spain
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Juan Agut;
Juan Agut
¶Departament de Química Inorgànica i Orgànica, Universitat Jaume I, Castelló, Spain
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Florenci V. González;
Florenci V. González
¶Departament de Química Inorgànica i Orgànica, Universitat Jaume I, Castelló, Spain
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Paula Ramos;
Paula Ramos
†Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Madrid, Spain
‡Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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Cobi Heijnen;
Cobi Heijnen
*Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
∥Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, U.S.A.
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Federico Mayor, Jr;
Federico Mayor, Jr
†Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Madrid, Spain
‡Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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Annemieke Kavelaars;
Annemieke Kavelaars
5
*Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands
∥Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, U.S.A.
5Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Cristina Murga
Cristina Murga
5
†Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Madrid, Spain
‡Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
5Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Publisher: Portland Press Ltd
Received:
February 01 2013
Revision Received:
February 04 2014
Accepted:
February 11 2014
Accepted Manuscript online:
February 11 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (3): 427–439.
Article history
Received:
February 01 2013
Revision Received:
February 04 2014
Accepted:
February 11 2014
Accepted Manuscript online:
February 11 2014
Citation
Hanneke L. D. M. Willemen, Pedro M. Campos, Elisa Lucas, Antonio Morreale, Rubén Gil-Redondo, Juan Agut, Florenci V. González, Paula Ramos, Cobi Heijnen, Federico Mayor, Annemieke Kavelaars, Cristina Murga; A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia. Biochem J 1 May 2014; 459 (3): 427–439. doi: https://doi.org/10.1042/BJ20130172
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