title: Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid arthritis.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences and Cardiovascular/Metabolic Diseases, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. steffar@wyeth.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Steffan
authors.forename: Edward
authors.initials: E
authors.lastname: Matelan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
authors.forename: William J
authors.initials: WJ
authors.lastname: Moore
authors.forename: William R
authors.initials: WR
authors.lastname: Solvibile
authors.forename: Eugene
authors.initials: E
authors.lastname: Trybulski
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Chadwick
authors.forename: Susan
authors.initials: S
authors.lastname: Chippari
authors.forename: Thomas
authors.initials: T
authors.lastname: Kenney
authors.forename: Amy
authors.initials: A
authors.lastname: Eckert
authors.forename: Lisa
authors.initials: L
authors.lastname: Borges-Marcucci
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Zhang
authors.initials: Z
authors.lastname: Xu
authors.forename: Lydia
authors.initials: L
authors.lastname: Mosyak
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Harnish
mesh_terms: 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
chemical_list: 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