4.7 Article

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

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 16, 页码 10992-11009

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00081

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资金

  1. Shanghai Science and Technology Commission Project [19ZR1448200, 21S11901500]
  2. Shanghai Talent Development funding Scheme [2020093]
  3. Shanghai Municipal Health Bureau young scientific research project [201940149]
  4. SKLDR/SIMM [SIMM2105KF-05]
  5. National Research Center for Translational Medicine at Shanghai

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Y1693, a small-molecule inhibitor of RANKL, was found to effectively prevent bone resorption and rescue alveolar bone loss caused by periodontal disease. It showed good tolerability and efficacy in an orally administered mouse model of osteoporosis.
Receptor activator of nuclear factor -KB (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 beta-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.

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