Control of chronic inflammation with pathway selective estrogen receptor ligands.
The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that 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 non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Steffan
Robert J
RJ
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA. steffar@wyeth.com
Matelan
Edward
E
Ashwell
Mark A
MA
Moore
William J
WJ
Solvibile
William R
WR
Trybulski
Eugene
E
Chadwick
Christopher C
CC
Chippari
Susan
S
Kenney
Thomas
T
Winneker
Richard C
RC
Eckert
Amy
A
Borges-Marcucci
Lisa
L
Adelman
Steven J
SJ
Xu
Zhang
Z
Mosyak
Lydia
L
Harnish
Douglas C
DC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002908:Chronic Disease; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology*; D008024:Ligands; D015394:Molecular Structure; D011720:Pyrazoles / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D011720:Pyrazoles; D011960:Receptors, Estrogen; C499198:WAY-169916