title: Benzobicyclooctanes as novel inhibitors of TNF-alpha signaling.
abstract: A novel series of TNF-alpha inhibitors based on a benzobicyclooctane scaffold is reported. The compounds display good potency in inhibiting TNF-alpha induced apoptosis and NF kappa B activation. Additionally, they are selective for TNF-alpha as they do not inhibit apoptosis induced by soluble Fas ligand. The compounds described here can act as leads for future medicinal chemistry efforts and may also be useful tools for elucidating the TNF-alpha signaling pathway.
authors.affiliation: Department of Chemical Genomics, Celltech R&D, Inc., 1631 220th Street SE, 98021, Bothell, WA 98021, USA. randy.jackson@verizon.com
authors.forename: Randy W
authors.initials: RW
authors.lastname: Jackson
authors.forename: Richard
authors.initials: R
authors.lastname: Gelinas
authors.forename: Ted A
authors.initials: TA
authors.lastname: Baughman
authors.forename: Thomas
authors.initials: T
authors.lastname: Cox
authors.forename: J Jeffry
authors.initials: JJ
authors.lastname: Howbert
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Kucera
authors.forename: John A
authors.initials: JA
authors.lastname: Latham
authors.forename: Fred
authors.initials: F
authors.lastname: Ramsdell
authors.forename: Devinder
authors.initials: D
authors.lastname: Singh
authors.forename: Ihab S
authors.initials: IS
authors.lastname: Darwish
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053222:Fas Ligand Protein; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008562:Membrane Glycoproteins / Q000494:pharmacology; D015394:Molecular Structure; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009795:Octanes / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009795:Octanes; D014409:Tumor Necrosis Factor-alpha