Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase.
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.
Gallagher
T F
TF
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
Seibel
G L
GL
Kassis
S
S
Laydon
J T
JT
Blumenthal
M J
MJ
Lee
J C
JC
Lee
D
D
Boehm
J C
JC
Fier-Thompson
S M
SM
Abt
J W
JW
Soreson
M E
ME
Smietana
J M
JM
Hall
R F
RF
Garigipati
R S
RS
Bender
P E
PE
Erhard
K F
KF
Krog
A J
AJ
Hofmann
G A
GA
Sheldrake
P L
PL
McDonnell
P C
PC
Kumar
S
S
Young
P R
PR
Adams
J L
JL
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
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