Development of an Orally Active Small-Molecule Inhibitor of Receptor Activator of Nuclear Factor-κB Ligand

Receptor activator of nuclear factor-κB (RANK)
and its ligand,
RANKL, play pivotal roles in bone remodeling. The monoclonal antibody
denosumab successfully inhibited the maturation of osteoclasts (OCs)
by binding to RANKL in the clinic. We continued our efforts to develop
small-molecule inhibitors of RANKL. In this work, 41 β-carboline
derivatives were synthesized based on previously synthesized compound Y1599 to improve its drug-like properties. Compound Y1693 was identified as a potent RANKL inhibitor that improved
absorption–distribution–metabolism–excretion
properties and effectively prevented RANKL-induced osteoclastogenesis
and bone resorption. Furthermore, Y1693 also suppressed
the expression of OC marker genes. Moreover, Y1693 demonstrated
good tolerability and efficacy in an orally administered mouse model
of osteoporosis as well as the ability to rescue alveolar bone loss
in vivo caused by periodontal disease. Collectively, the above findings
may provide a valuable direction for the development of novel antiresorptive
therapies that target RANKL.