title: p38 mitogen-activated protein kinase inhibitors--mechanisms and therapeutic potentials.
abstract: The pyridinylimidazole compounds, exemplified by SB 203580, originally were prepared as inflammatory cytokine synthesis inhibitors. Subsequently, the compounds were found to be selective inhibitors for p38 mitogen-activated protein kinase (MAPK), a member of the MAPK family. SB 203580 inhibits the catalytic activity of p38 MAPK by competitive binding in the ATP pocket. Four homologues of p38 MAPK have been identified to date, and interestingly, their biochemical properties and their respective sensitivities to the inhibitors are distinct. X-ray crystallographic analysis of p38-inhibitor complexes reinforces the observations made from site-directed mutagenesis studies, thereby providing a molecular basis for understanding the kinase selectivity of these inhibitors. The p38 MAPK inhibitors are efficacious in several disease models, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury.
authors.affiliation: Smithkline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Kassis
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: A
authors.initials: A
authors.lastname: Badger
authors.forename: J L
authors.initials: JL
authors.lastname: Adams
mesh_terms: D018925:Chemokines / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005544:Forecasting; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D008934:Mitogens / Q000502:physiology*; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
chemical_list: D018925:Chemokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008934:Mitogens; D011725:Pyridines; D011726:Pyridinium Compounds; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580