title: A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia.
abstract: 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.
authors: *Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Hanneke L D M
authors: HL
authors: Willemen
authors: †Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" UAM-CSIC, Madrid, Spain.
authors: Pedro M
authors: PM
authors: Campos
authors: Elisa
authors: E
authors: Lucas
authors: §Centro de Biología Molecular "Severo Ochoa", UAM-CSIC, Madrid, Spain.
authors: Antonio
authors: A
authors: Morreale
authors: §Centro de Biología Molecular "Severo Ochoa", UAM-CSIC, Madrid, Spain.
authors: Rubén
authors: R
authors: Gil-Redondo
authors: ¶Departament de Química Inorgànica i Orgànica, Universitat Jaume I, Castelló, Spain.
authors: Juan
authors: J
authors: Agut
authors: ¶Departament de Química Inorgànica i Orgànica, Universitat Jaume I, Castelló, Spain.
authors: Florenci V
authors: FV
authors: González
authors: Paula
authors: P
authors: Ramos
authors: Cobi
authors: C
authors: Heijnen
authors: Federico
authors: F
authors: Mayor
authors: Annemieke
authors: A
authors: Kavelaars
authors: Cristina
authors: C
authors: Murga
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; C000588679:N-(5-chloro-2-methylphenyl)-7-nitrobenzo(c)(1,2,5)oxadiazol-4-amine; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases