1-Substituted 4-Aryl-5-pyridinylimidazoles:  A New Class of Cytokine Suppressive Drugs with Low 5-Lipoxygenase and Cyclooxygenase Inhibitory Potency

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cas...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-09, Vol.39 (20), p.3929-3937
Main Authors: Boehm, Jeffrey C, Smietana, Juanita M, Sorenson, Margaret E, Garigipati, Ravi S, Gallagher, Timothy F, Sheldrake, Peter L, Bradbeer, Jeremy, Badger, Alison M, Laydon, Jeffrey T, Lee, John C, Hillegass, Leonard M, Griswold, Donald E, Breton, John J, Chabot-Fletcher, Marie C, Adams, Jerry L
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Arachidonate 5-Lipoxygenase - metabolism
Arachidonic Acid - metabolism
Arthritis - drug therapy
Biological and medical sciences
Bone Density - drug effects
Bones, joints and connective tissue. Antiinflammatory agents
Cyclooxygenase Inhibitors
Cytokines - antagonists & inhibitors
Imidazoles - chemical synthesis
Imidazoles - metabolism
Imidazoles - pharmacology
Lipoxygenase Inhibitors
Medical sciences
Mice
Mice, Inbred BALB C
Molecular Structure
Morpholines - chemical synthesis
Morpholines - metabolism
Morpholines - pharmacology
Pharmacology. Drug treatments
Prostaglandin-Endoperoxide Synthases - metabolism
Protein Kinases - metabolism
Rats
Structure-Activity Relationship
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - biosynthesis
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Summary:A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm960415o