Abstract
Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / pathology
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Arthritis, Rheumatoid / drug therapy*
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Cell Line
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Estrogen Receptor alpha / chemistry
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Estrogen Receptor alpha / drug effects
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Estrogen Receptor alpha / metabolism
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Estrogen Receptor beta / chemistry
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Estrogen Receptor beta / drug effects
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Estrogen Receptor beta / metabolism
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Humans
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indazoles / pharmacology
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Ligands
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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NF-kappa B / biosynthesis
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NF-kappa B / genetics
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Phenols / chemical synthesis*
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Phenols / chemistry
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Phenols / pharmacology
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Rats
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Rats, Inbred Lew
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Receptors, Estrogen / chemistry
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Receptors, Estrogen / drug effects*
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Receptors, Estrogen / metabolism
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Indazoles
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Ligands
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NF-kappa B
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Phenols
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Receptors, Estrogen