Development and characterization of biphenylsulfonamides as novel inhibitors of bone resorption.
Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and that prevent ovariectomy-induced bone loss in vivo. A number of aromatic substituted derivatives were prepared and a QSAR model was generated, which allowed accurate prediction of compound potency. Using this model, we have prepared compounds able to inhibit osteoclast formation and bone resorption in vitro at concentrations in the nanomolar range. One such compound, 55 (ABD295) (Greig, I. R.; Mohamed, A. I.; Ralston, S. H.; van't Hof, R. J. Alkyl Aryl Sulfonamides as Therapeutic Agents for the Treatment of Bone Conditions. GB Patent WO2005118528, 2005), fully reversed ovariectomy-induced bone loss in mice at a dose of 5 (mg/kg)/day. In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption.
Greig
Iain R
IR
School of Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. i.greig@abdn.ac.uk
Idris
Aymen I
AI
Ralston
Stuart H
SH
van't Hof
Rob J
RJ
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010052:Ovariectomy; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C517241:2',4'-difluoro-2-methylbiphenyl-4-sulfonic acid (4-hydroxybutyl)amide; D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; D013449:Sulfonamides