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ID: ALA4665827

Journal: J Med Chem

Title: Discovery of Small-Molecule Inhibitors of Receptor Activator of Nuclear Factor-κB Ligand with a Superior Therapeutic Index.

Authors: Rinotas V,Papakyriakou A,Violitzi F,Papaneophytou C,Ouzouni MD,Alexiou P,Strongilos A,Couladouros E,Kontopidis G,Eliopoulos E,Douni E

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 LC to IC ratio. These RANKL-selective inhibitors are an excellent starting point for the development of small-molecule therapeutics against osteolytic diseases.

CiteXplore: 32955874

DOI: 10.1021/acs.jmedchem.0c01316