Estrogen Receptor Dependent Inhibitors of NF-κB Transcriptional Activation-1 Synthesis and Biological Evaluation of Substituted 2-Cyanopropanoic Acid Derivatives: Pathway Selective Inhibitors of NF-κB, a Potential Treatment for Rheumatoid Arthritis

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.