Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity.
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.
Chadwick
Christopher C
CC
Women's Health Research Institute and Departmens of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Chippari
Susan
S
Matelan
Edward
E
Borges-Marcucci
Lisa
L
Eckert
Amy M
AM
Keith
James C
JC
Albert
Leo M
LM
Leathurby
Yelena
Y
Harris
Heather A
HA
Bhat
Ramesh A
RA
Ashwell
Mark
M
Trybulski
Eugene
E
Winneker
Richard C
RC
Adelman
Steven J
SJ
Steffan
Robert J
RJ
Harnish
Douglas C
DC
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
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