WAY-204688

WAY-204688 is an estrogen receptor (ER-α) selective, orally active inhibitor of NF-κB transcriptional activity with an IC₅₀ of 122 ± 30 nM for NF-κB-luciferase (NF-κB-luc) in HAECT-1 cells. IC50 & Target: IC50:122±30 nM (NF-κB)^[1] In Vitro: WAY-204688 is ER-dependenrt (activity seen only when hER is coexpressed with NF-κB-luciferase in human aortic endothelial cell lines (HAECT-1) cells). The interaction of WAY-204688 with ERα and ERβ is examined in vitro. WAY-204688 displaces [³H]E2 from the ERα ligand binding domain protein (LBD) with IC₅₀=2.43 μM and from the ERβ ligand binding domain protein (LBD) with IC₅₀=1.5 μM^[1]. In Vivo: WAY-204688 (5 mg/kg per day, po daily for 5 weeks) is evaluated in vivo for the ability to inhibit four proinflammatory genes (MHC, invariant chain (MHI), VCAM-1, RANTES, and TNF-α). The effect of WAY-204688 on induction of the gene products and on uterine wet weight is compared to that of 17α-ethinyl 17β-estradiol (EE at 10 μg/kg per day) in the same paradigm. Further characterization of WAY-204688 is carried out in several preclinical models of inflammatory disease. In the Lewis rat adjuvant-induced arthritis model (AIA), WAY-204688 is active at a dose of 0.3 mg/kg per day, po^[1].