Inhibitors of p38 Mitogen-Activated Protein Kinase

Asthma is an inflammatory disease of the airways, which in patients with mild to moderate symptoms is adequately controlled by either β2-adrenoceptor agonists or corticosteroids, or a combination of both. Despite this, there are classes of patients that fail to respond to these treatments. In addition, there is a general trend towards increasing morbidity and mortality due to asthma, which suggests that there is a need for new and improved treatments. The p38 mitogen-activated protein kinases (MAPKs) represent a point of convergence for multiple signalling processes that are activated in inflammation and that impact on a diverse range of events that are important in inflammation. Small molecule pyridinyl imidazole inhibitors of p38 MAPK have proved to be highly effective in reducing various parameters of inflammation, in particular cytokine expression. Like corticosteroids, inhibitors of p38 MAPK appear to be able to repress gene expression at multiple levels, for example, by transcriptional, posttranscriptional and translational repression, and this raises the possibility of a similarly broad spectrum of anti-inflammatory activities. Indeed these molecules have proved to be effective in numerous in vitro and in vivo models of inflammation and septicaemia, which suggests that such compounds may be effective as therapeutic agents against inflammatory disorders. Despite these very promising indications of the possible therapeutic use of p38 MAPK inhibitors, a number of events that are p38-dependent are in fact also beneficial to the resolution or modulation of diseases such as asthma. We conclude that the overall effect of p38 MAPK inhibition would be beneficial in inflammatory diseases such as rheumatoid arthritis and asthma. However, these drugs may result in a complex phenotype that will require careful evaluation. Currently, a number of second or third generation inhibitors of p38 MAPK are being tested in phase I and phase II clinical trials.