Since the discovery of p38 MAP kinase in 1994, our understanding of its biology has
progressed dramatically. The key advances include (1) identification of p38 MAP kinase
homologs and protein kinases that act upstream and downstream from p38 MAP kinase,
(2) identification of interesting and potentially important substrates, (3) elucidation
of the role of p38 MAP kinase in cellular processes and (4) the establishment of the
mechanism by which the pyridinylimidazole p38 MAP kinase inhibitors inhibit enzyme
activity. It is now known that there are four members of the p38 MAP kinase family.
They differ in their tissue distribution, regulation of kinase activation and subsequent
phosphorylation of downstream substrates. They also differ in terms of their sensitivities
toward the p38 MAP kinase inhibitors. The best-studied isoform is p38 alpha, whose
activation has been observed in many hematopoietic and non-hematopoietic cell types
upon treatment with appropriate stimuli. The pyridinylimidazole compounds, exemplified
by SB 203580, were originally prepared as inflammatory cytokine synthesis inhibitors
that subsequently were found to be selective inhibitors of p38 MAP kinase. SB 203580
inhibits the catalytic activity of p38 MAP kinase by competitive binding in the ATP
pocket. X-ray crystallographic studies of the target enzyme complexed with inhibitor
reinforce the observations made from site-directed mutagenesis studies, thereby providing
a molecular basis for understanding the kinase selectivity of these inhibitors. The
p38 MAP kinase inhibitors are efficacious in several disease models, including inflammation,
arthritis and other joint diseases, septic shock, and myocardial injury. In all cases,
p38 activation in key cell types correlated with disease initiation and progression.
Treatment with p38 MAP kinase inhibitors attenuated both p38 activation and disease
severity. Structurally diverse p38 MAP kinase inhibitors have been tested extensively
in preclinical studies.