dc.creator | Rinotas V., Papakyriakou A., Violitzi F., Papaneophytou C., Ouzouni M.-D., Alexiou P., Strongilos A., Couladouros E., Kontopidis G., Eliopoulos E., Douni E. | en |
dc.date.accessioned | 2023-01-31T09:51:34Z | |
dc.date.available | 2023-01-31T09:51:34Z | |
dc.date.issued | 2020 | |
dc.identifier | 10.1021/acs.jmedchem.0c01316 | |
dc.identifier.issn | 00222623 | |
dc.identifier.uri | http://hdl.handle.net/11615/78518 | |
dc.description.abstract | Receptor activator of nuclear factor-κB ligand (RANKL) constitutes the master mediator of osteoclastogenesis, while its pharmaceutical inhibition by a monoclonal antibody has been approved for the treatment of postmenopausal osteoporosis. To date, the pursuit of pharmacologically more favorable approaches using low-molecular-weight inhibitors has been hampered by low specificity and high toxicity issues. This study aimed to discover small-molecule inhibitors targeting RANKL trimer formation. Through a systematic screening of 39 analogues of SPD-304, a dual inhibitor of tumor necrosis factor (TNF) and RANKL trimerization, we identified four compounds (1b, 3b, 4a, and 4c) that selectively inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, without affecting TNF activity or osteoblast differentiation. Based on structure-activity observations extracted from the most potent and less toxic inhibitors of RANKL-induced osteoclastogenesis, we synthesized a focused set of compounds that revealed three potent inhibitors (19a, 19b, and 20a) with remarkably low cell-toxicity and improved therapeutic indexes as shown by the LC50 to IC50 ratio. These RANKL-selective inhibitors are an excellent starting point for the development of small-molecule therapeutics against osteolytic diseases. © | en |
dc.language.iso | en | en |
dc.source | Journal of Medicinal Chemistry | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85094222341&doi=10.1021%2facs.jmedchem.0c01316&partnerID=40&md5=feba22da39779e802beabe3656ca577d | |
dc.subject | (1 ((3 nitrophenyl)sulfonyl) 1h indol 3 yl) (4 phenylsulfonyl)piperazin 1 yl)methanone | en |
dc.subject | indole derivative | en |
dc.subject | n (2 ((4 cyano n methylphenyl)sulfonamido)ethyl) n methyl 1 ((3 nitrophenyl)sulfonyl) 1h indole 3 carboxamide | en |
dc.subject | n methyl n (2 (n methylphenylsulfonamido)ethyl) 1 ((3 nitrophenyl)sulfonyl) 1h indole 3 carboxamide | en |
dc.subject | nitro derivative | en |
dc.subject | osteoclast differentiation factor | en |
dc.subject | piperazine derivative | en |
dc.subject | small molecule transport agent | en |
dc.subject | spd 304 | en |
dc.subject | sulfonamide | en |
dc.subject | tumor necrosis factor | en |
dc.subject | tumor necrosis factor inhibitor | en |
dc.subject | unclassified drug | en |
dc.subject | chroman derivative | en |
dc.subject | indole derivative | en |
dc.subject | ligand | en |
dc.subject | osteoclast differentiation factor | en |
dc.subject | SPD-304 | en |
dc.subject | TNFSF11 protein, human | en |
dc.subject | animal cell | en |
dc.subject | Article | en |
dc.subject | binding affinity | en |
dc.subject | controlled study | en |
dc.subject | crystal structure | en |
dc.subject | cytotoxicity | en |
dc.subject | drug design | en |
dc.subject | drug potency | en |
dc.subject | drug protein binding | en |
dc.subject | drug screening | en |
dc.subject | drug selectivity | en |
dc.subject | drug synthesis | en |
dc.subject | drug targeting | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | IC50 | en |
dc.subject | LC50 | en |
dc.subject | molecular model | en |
dc.subject | mouse | en |
dc.subject | nonhuman | en |
dc.subject | osteoblast | en |
dc.subject | osteoclastogenesis | en |
dc.subject | osteolysis | en |
dc.subject | structure activity relation | en |
dc.subject | therapeutic index | en |
dc.subject | trimerization | en |
dc.subject | animal | en |
dc.subject | bone development | en |
dc.subject | cell survival | en |
dc.subject | chemical structure | en |
dc.subject | chemistry | en |
dc.subject | dose response | en |
dc.subject | drug development | en |
dc.subject | drug effect | en |
dc.subject | metabolism | en |
dc.subject | molecular dynamics | en |
dc.subject | molecular library | en |
dc.subject | pharmacology | en |
dc.subject | synthesis | en |
dc.subject | therapeutic index | en |
dc.subject | Animals | en |
dc.subject | Cell Survival | en |
dc.subject | Chromans | en |
dc.subject | Dose-Response Relationship, Drug | en |
dc.subject | Drug Discovery | en |
dc.subject | Humans | en |
dc.subject | Indoles | en |
dc.subject | Ligands | en |
dc.subject | Mice | en |
dc.subject | Molecular Dynamics Simulation | en |
dc.subject | Molecular Structure | en |
dc.subject | Osteogenesis | en |
dc.subject | RANK Ligand | en |
dc.subject | Small Molecule Libraries | en |
dc.subject | Structure-Activity Relationship | en |
dc.subject | Therapeutic Index | en |
dc.subject | American Chemical Society | en |
dc.title | Discovery of Small-Molecule Inhibitors of Receptor Activator of Nuclear Factor-κB Ligand with a Superior Therapeutic Index | en |
dc.type | journalArticle | en |