Discovery of biphenylketones as dual modulators of inflammation and bone loss.
Biphenylketones were identified as novel inhibitors of NFkappaB activation. Structure-activity studies led to the identification of compound 4c, which had good potency against osteoclasts (IC50=0.8 microM), showed oral activity, and was able to completely prevent inflammation and bone loss in vivo.
Greig
Iain R
IR
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. i.greig@abdn.ac.uk
Coste
Emmanuel
E
Ralston
Stuart H
SH
van't Hof
Rob J
RJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy*; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010024:Osteoporosis / Q000188:drug therapy*; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000893:Anti-Inflammatory Agents; D001555:Benzene Derivatives; D007659:Ketones; D016328:NF-kappa B; D011084:Polycyclic Aromatic Hydrocarbons; D014409:Tumor Necrosis Factor-alpha