Estrogen Receptor Dependent Inhibitors Of Nf-Kappa B Transcriptional Activation-1 Synthesis And Biological Evaluation Of Substituted 2-Cyanopropanoic Acid Derivatives: Pathway Selective Inhibitors Of Nf-Kappa B, A Potential Treatment For Rheumatoid Arthritis

Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF kappa B. 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.