title: The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-kappa B transcriptional activity in models of rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial proliferation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-kappaB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 transgenic rat and the Lewis rat adjuvant-induced model, after daily oral administration. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, alpha1-acid glycoprotein (alpha1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstrate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-alpha-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-kappaB transcriptional activity.
authors.affiliation: Cardiovascular and Metabolic Disease Research, Wyeth Research, Cambridge, MA, USA. jkeith@wyeth.com
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: Max
authors.initials: M
authors.lastname: Follettie
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Borges-Marcucci
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Chadwick
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; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects* / Q000502:physiology
chemical_list: D008024:Ligands; D016328:NF-kappa B; D011720:Pyrazoles; D011960:Receptors, Estrogen; C499198:WAY-169916