Discovery of novel benzopyranyl tetracycles that act as inhibitors of osteoclastogenesis induced by receptor activator of NF-κB ligand.
A novel benzopyran-fused molecular framework 7ai was discovered as a specific inhibitor of RANKL-induced osteoclastogenesis using a cell-based TRAP activity assay from drug-like small-molecule libraries constructed by diversity-oriented synthesis. Its inhibitory activity was confirmed by in vitro evaluations including specific inhibition of RANKL-induced ERK phosphorylation and NF-κB transcriptional activation. 7ai can serve as a specific small-molecule modulator for mechanistic studies of RANKL-induced osteoclast differentiation as well as a potential lead for the development of antiresorptive drugs.
Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
Mingyan
M
Zhu
Myung Hee
MH
Kim
Sanghee
S
Lee
Su Jung
SJ
Bae
Seong Hwan
SH
Kim
Seung Bum
SB
Park
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation; D053245:RANK Ligand / Q000494:pharmacology / Q000502:physiology*; D054852:Small Molecule Libraries; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D050071:Bone Density Conservation Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D016328:NF-kappa B; D053245:RANK Ligand; D054852:Small Molecule Libraries; D048049:Extracellular Signal-Regulated MAP Kinases