Benzobicyclooctanes as novel inhibitors of TNF-alpha signaling.
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.
Jackson
Randy W
RW
Department of Chemical Genomics, Celltech R&D, Inc., 1631 220th Street SE, 98021, Bothell, WA 98021, USA. randy.jackson@verizon.com
Gelinas
Richard
R
Baughman
Ted A
TA
Cox
Thomas
T
Howbert
J Jeffry
JJ
Kucera
Kristin A
KA
Latham
John A
JA
Ramsdell
Fred
F
Singh
Devinder
D
Darwish
Ihab S
IS
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
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009795:Octanes; D014409:Tumor Necrosis Factor-alpha