Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China.
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
J Med Chem. 2022 Aug 25;65(16):10992-11009. doi: 10.1021/acs.jmedchem.2c00081. Epub 2022 Aug 12.
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 to improve its drug-like properties. Compound was identified as a potent RANKL inhibitor that improved absorption-distribution-metabolism-excretion properties and effectively prevented RANKL-induced osteoclastogenesis and bone resorption. Furthermore, also suppressed the expression of OC marker genes. Moreover, 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.
核因子-κB 受体激活剂（RANK）及其配体 RANKL 在骨重塑中发挥着关键作用。单克隆抗体地舒单抗通过与 RANKL 结合，在临床上成功抑制破骨细胞（OC）的成熟。我们继续努力开发 RANKL 的小分子抑制剂。在这项工作中，基于先前合成的化合物 ，我们合成了 41 个 β-咔啉衍生物，以改善其类药性。化合物 被鉴定为一种有效的 RANKL 抑制剂，可改善吸收-分布-代谢-排泄特性，并有效抑制 RANKL 诱导的破骨细胞生成和骨吸收。此外， 还抑制了 OC 标记基因的表达。此外， 在骨质疏松症的口服给药小鼠模型中表现出良好的耐受性和疗效，并且能够在体内挽救牙周病引起的牙槽骨丢失。综上所述，这些发现可能为开发针对 RANKL 的新型抗吸收疗法提供有价值的方向。
