Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid arthritis.
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.
Steffan
Robert J
RJ
Chemical and Screening Sciences and Cardiovascular/Metabolic Diseases, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 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
Eckert
Amy
A
Borges-Marcucci
Lisa
L
Keith
James C
JC
Xu
Zhang
Z
Mosyak
Lydia
L
Harnish
Douglas C
DC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011960:Receptors, Estrogen / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007191:Indazoles; D008024:Ligands; D016328:NF-kappa B; D010636:Phenols; D011960:Receptors, Estrogen