title: Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1.
abstract: To inhibit arthritis upstream of inflammatory cytokine release and matrix metalloproteinase (MMP) action, we designed de novo a small-molecule inhibitor of c-Fos/activator protein-1 (AP-1) using three-dimensional (3D) pharmacophore modeling. This model was based on the 3D structure of the basic region-leucine zipper domain of AP-1-DNA complex. Administration of this inhibitor prevented type II collagen-induced arthritis from day 21, before the onset of arthritis, or from day 27, resolved arthritis after its onset. Suppression of disease was accomplished by reducing the amounts of inflammatory cytokines and MMPs in vivo in sera and joints and in vitro in synovial cell and chondrocyte cultures. The primary action of this molecule was the inhibition of matrix-degrading MMPs and inflammatory cytokines including interleukin 1beta; this molecule also synergized with anti-tumor necrosis factor alpha to inhibit arthritis. Thus, selective inhibition of c-Fos/AP-1 resolves arthritis in a preclinical model of the disease.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., 4-1 Shimookui 2-chome, Toyama 930-8508, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Aikawa
authors.forename: Kimiko
authors.initials: K
authors.lastname: Morimoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Chaki
authors.forename: Akira
authors.initials: A
authors.lastname: Hashiramoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Narita
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shiozawa
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004220:Disulfides / Q000008:administration & dosage*; D016762:Genes, fos / Q000187:drug effects*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D004220:Disulfides; D018808:Transcription Factor AP-1