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PMID: 9043657 Published · ppublish English Journal Article

Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase.

Bioorganic & medicinal chemistry ·Vol. 5 ·No. 1 ·1997-01-00 ·Pages 49-64

Gallagher TF, Seibel GL, Kassis S, Laydon JT, Blumenthal MJ, Lee JC, Lee D, Boehm JC, Fier-Thompson SM, Abt JW, Soreson ME, Smietana JM, Hall RF, Garigipati RS, Bender PE, Erhard KF, Krog AJ, Hofmann GA, Sheldrake PL, McDonnell PC, Kumar S, Young PR, Adams JL

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.

MeSH Terms

Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors Cell Line Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors Cytokines/biosynthesis Enzyme Inhibitors/pharmacology Humans Imidazoles/chemistry,pharmacology Isoenzymes/antagonists & inhibitors Magnetic Resonance Spectroscopy Mass Spectrometry Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases/antagonists & inhibitors Models, Molecular Protein Kinase C/antagonists & inhibitors Protein Kinase C-alpha Stress, Physiological/metabolism Structure-Activity Relationship p38 Mitogen-Activated Protein Kinases

Chemicals

Cytokines Enzyme Inhibitors Imidazoles Isoenzymes Cyclic AMP-Dependent Protein Kinases PRKCA protein, human Protein Kinase C Protein Kinase C-alpha Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases

Authors & Affiliations

23 authors, click to expand affiliations / ORCID

Gallagher T F

Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.

Seibel G L

Kassis S

Laydon J T

Blumenthal M J

Lee J C

Lee D

Boehm J C

Fier-Thompson S M

Abt J W

Soreson M E

Smietana J M

Hall R F

Garigipati R S

Bender P E

Erhard K F

Krog A J

Hofmann G A

Sheldrake P L

McDonnell P C

Kumar S

Young P R

Adams J L

Article Info

Journal

Bioorganic & medicinal chemistry

Abbr.

Bioorg Med Chem

ISSN

0968-0896

DOI

10.1016/s0968-0896(96)00212-x

Published

1997-01-00

Pages

49-64

Language

English

Region

England

NLM ID

9413298

Subset

External Links

PubMed source DOI: 10.1016/s0968-0896(96)00212-x View journal details

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Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase.

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