| First Author | Willemen HL | Year | 2014 |
| Journal | Biochem J | Volume | 459 |
| Issue | 3 | Pages | 427-39 |
| PubMed ID | 24517375 | Mgi Jnum | J:212293 |
| Mgi Id | MGI:5578437 | Doi | 10.1042/BJ20130172 |
| Citation | Willemen HL, et al. (2014) A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia. Biochem J 459(3):427-39 |
| abstractText | 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 TNFalpha (tumour necrosis factor alpha) 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 IC(5)(0) value of 1.8 muM (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. |
