Synthesis and Activity of Substituted 4-(Indazol-3-yl)phenols as Pathway-Selective Estrogen Receptor Ligands Useful in the Treatment of Rheumatoid Arthritis

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.