Abstract
Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.
MeSH terms
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Administration, Oral
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Animals
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Animals, Genetically Modified
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antirheumatic Agents / chemical synthesis*
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Antirheumatic Agents / chemistry
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Antirheumatic Agents / pharmacology
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / pathology
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Cell Line
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Creatine Kinase / metabolism
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Crystallography, X-Ray
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / physiology*
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Estrogen Receptor beta / genetics
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Estrogen Receptor beta / physiology*
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Humans
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Inflammatory Bowel Diseases / drug therapy
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Luciferases / genetics
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Mice
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / biosynthesis
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NF-kappa B / genetics
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Nitriles / chemical synthesis*
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Nitriles / chemistry
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Nitriles / pharmacology
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Propionates / chemical synthesis*
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Propionates / chemistry
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Propionates / pharmacology
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Rats
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Rats, Inbred Lew
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
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Transcriptional Activation
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antirheumatic Agents
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Estrogen Receptor alpha
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Estrogen Receptor beta
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NF-kappa B
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Nitriles
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Propionates
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Luciferases
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Creatine Kinase