Structure-activity relationships of p38 mitogen-activated protein kinase inhibitors

Rheumatoid arthritis and other chronic inflammatory diseases constitute a major therapeutic challenge, usually not sufficiently met by the classical antiinflammatory medications. Recent research efforts provided new insights into the molecular basis of these pathologies and disclosed new opportunities for developing improved drugs directed to the chemical mediators of the disease. The enzyme p38 MAP kinase plays a central role in the signal transduction cascade that leads to the production of both the proinflammatory cytokines, TNF-alpha and IL-1 beta, thus representing an attractive therapeutic target for novel antiinflammatory therapies. A number of p38 inhibitors belonging to different structural families have been developed as potential antiinflammatory drugs, and some of them progressed into clinical trials. The initial pyridinyl imidazole inhibitors contributed to the identification and characterization of p38 MAP kinase as the molecular target of these new drugs, and were found to act as competitive inhibitors at the ATP binding site of the enzyme. A number of variations in the pyridine and imidazole rings were subsequently introduced. Other inhibitors structurally unrelated to the pyridinylimidazoles have also been developed, such as the pyridopyridazinones, diaryl ureas, aminobenzophenones and aromatic amides. One of these structural classes, the N,N'-diarylureas, has been found to interact with a distinct allosteric site of p38 MAP kinase and requires a deep conformational change prior to binding.