title: Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase.
abstract: Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKC alpha and ERK kinase activity is observed.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Gallagher
authors.forename: G L
authors.initials: GL
authors.lastname: Seibel
authors.forename: S
authors.initials: S
authors.lastname: Kassis
authors.forename: J T
authors.initials: JT
authors.lastname: Laydon
authors.forename: M J
authors.initials: MJ
authors.lastname: Blumenthal
authors.forename: J C
authors.initials: JC
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: J C
authors.initials: JC
authors.lastname: Boehm
authors.forename: S M
authors.initials: SM
authors.lastname: Fier-Thompson
authors.forename: J W
authors.initials: JW
authors.lastname: Abt
authors.forename: M E
authors.initials: ME
authors.lastname: Soreson
authors.forename: J M
authors.initials: JM
authors.lastname: Smietana
authors.forename: R F
authors.initials: RF
authors.lastname: Hall
authors.forename: R S
authors.initials: RS
authors.lastname: Garigipati
authors.forename: P E
authors.initials: PE
authors.lastname: Bender
authors.forename: K F
authors.initials: KF
authors.lastname: Erhard
authors.forename: A J
authors.initials: AJ
authors.lastname: Krog
authors.forename: G A
authors.initials: GA
authors.lastname: Hofmann
authors.forename: P L
authors.initials: PL
authors.lastname: Sheldrake
authors.forename: P C
authors.initials: PC
authors.lastname: McDonnell
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: P R
authors.initials: PR
authors.lastname: Young
authors.forename: J L
authors.initials: JL
authors.lastname: Adams
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051571:Protein Kinase C-alpha; D013312:Stress, Physiological / Q000378:metabolism*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D017868:Cyclic AMP-Dependent Protein Kinases; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases