title: Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity.
abstract: Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-kappaB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.
authors.affiliation: Women's Health Research Institute and Departmens of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Chadwick
authors.forename: Susan
authors.initials: S
authors.lastname: Chippari
authors.forename: Edward
authors.initials: E
authors.lastname: Matelan
authors.forename: Lisa
authors.initials: L
authors.lastname: Borges-Marcucci
authors.forename: Amy M
authors.initials: AM
authors.lastname: Eckert
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Leo M
authors.initials: LM
authors.lastname: Albert
authors.forename: Yelena
authors.initials: Y
authors.lastname: Leathurby
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harris
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Bhat
authors.forename: Mark
authors.initials: M
authors.lastname: Ashwell
authors.forename: Eugene
authors.initials: E
authors.lastname: Trybulski
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Adelman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Steffan
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Harnish
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015796:HLA-B27 Antigen / Q000235:genetics; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015796:HLA-B27 Antigen; D008024:Ligands; D016328:NF-kappa B; D011720:Pyrazoles; D011960:Receptors, Estrogen; C499198:WAY-169916