1-Substituted 4-Aryl-5-pyridinylimidazoles: A New Class of Cytokine Suppressive Drugs with Low 5-Lipoxygenase and Cyclooxygenase Inhibitory Potency
| Autor: | Jeremy Bradbeer, Margaret E. Sorenson, Jerry L. Adams, Marie Chabot-Fletcher, John J. Breton, Donald E. Griswold, Timothy Francis Gallagher, L. M. Hillegass, Alison M. Badger, Ravi Shanker Garigipati, Juanita M. Smietana, Peter L. Sheldrake, John C. Lee, Jeffrey T. Laydon, Jeffrey C. Boehm |
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| Rok vydání: | 1996 |
| Předmět: |
Morpholines
medicine.medical_treatment Pharmacology Proinflammatory cytokine Mice Structure-Activity Relationship Bone Density Drug Discovery medicine Animals Cyclooxygenase Inhibitors Lipoxygenase Inhibitors Protein kinase A chemistry.chemical_classification Mice Inbred BALB C Arachidonate 5-Lipoxygenase Arachidonic Acid Molecular Structure biology Tumor Necrosis Factor-alpha Chemistry Kinase Arthritis Monocyte Anti-Inflammatory Agents Non-Steroidal Imidazoles Rats Cytokine Enzyme medicine.anatomical_structure Prostaglandin-Endoperoxide Synthases Enzyme inhibitor Arachidonate 5-lipoxygenase biology.protein Cytokines Molecular Medicine Protein Kinases |
| Zdroj: | Journal of Medicinal Chemistry. 39:3929-3937 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm960415o |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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