p38α mitogen-activated protein kinase inhibitors as anti-inflammatory agents

p38α MAPK is an intracellular serine/threonine protein kinase that regulates many physiological processes including the biosynthesis of inflammatory cytokines. Elevated levels of inflammatory cytokines have been implicated in the pathogenesis of several chronic diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and cardiovascular disease. Recently, the use of biologics to modulate cytokines has shown efficacy in treating some of these diseases. Therefore, it is expected that orally active inhibitors of p38α MAPK will demonstrate similar therapeutic effects and present an attractive alternative for the treatment of chronic inflammatory diseases. This research uses a computer-assisted structure-based design approach for the development of p38α MAPK inhibitors. A series of ligands were designed and docked into a crystal structure model. Compounds were synthesised and evaluated in enzyme and cellular assays. A number of these compounds were found to inhibit p38α MAPK and exhibit potent anti-inflammatory activity.