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

Abstract

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.

Harnessing the cyclization strategy for new drug discovery

“…Interestingly, cyclization of compound Y1599 gave the β -carboline analog Y1693, which exhibited excellent osteoclastogenesis inhibition (89% at 1 μmol/L) and low toxicity. Y1693 markedly reversed OVX-induced osteoporosis after oral administration and could be used as a promising candidate for antiresorptive therapies 88 .

Figure 13 The discovery of novel orally active RANK inhibitor Y1693 via the cyclization strategy.

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Mechanistic advances in osteoporosis and anti‐osteoporosis therapies

“…Orally, Y1693 demonstrates good tolerability and efficacy in OVX mice and could also suppress the expression of osteoclast marker genes. 200 In addition, another verteporfin analog shows a dose-dependent inhibition of RANK-RANKL interaction in a competitive ELISA. 201 However, its specificity has not been tested, and there is a lack of in vivo data.…”

“…Compound Y1599 is further cyclized and oxidized to obtain Y1693. Orally, Y1693 demonstrates good tolerability and efficacy in OVX mice and could also suppress the expression of osteoclast marker genes 200 . In addition, another verteporfin analog shows a dose‐dependent inhibition of RANK–RANKL interaction in a competitive ELISA 201 .…”