Development of an Orally Active Small-Molecule Inhibitor of Receptor Activator of Nuclear Factor-?B Ligand
文献类型：期刊论文
| 作者 | Yang, Kai3; Li, Shunyao2; Wang, Tianqi3; Yan, Xueming3; He, Qian2 ; Ning, Ruonan3; Xu, Xing3; Yao, Wei1; Zhang, Xiaofei2; Yang, Chunhao2
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2022-08-25 |
| 卷号 | 65期号:16页码:10992-11009 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c00081 |
| 通讯作者 | Zhang, Xiaofei(xiaofeizhang@simm.ac.cn) ; Yang, Chunhao(chyang@simm.ac.cn) ; Jiang, Min(jiangm263@163.com) |
| 英文摘要 | 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. |
| WOS关键词 | OSTEOCLAST DIFFERENTIATION ; BONE-RESORPTION ; OSTEOPROTEGERIN ; DENOSUMAB ; RANKL ; REGENERATION ; ELUCIDATION ; DISEASE ; CANCER ; WOMEN |
| 资助项目 | Shanghai Science and Technology Commission Project[19ZR1448200] ; Shanghai Science and Technology Commission Project[21S11901500] ; Shanghai Talent Development funding Scheme[2020093] ; Shanghai Municipal Health Bureau young scientific research project[201940149] ; SKLDR/SIMM[SIMM2105KF-05] ; National Research Center for Translational Medicine at Shanghai |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000841501700001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302275]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Xiaofei; Yang, Chunhao; Jiang, Min |
| 作者单位 | 1.Univ Calif Davis, Ctr Musculoskeletal Hlth, Dept Internal Med, Med Ctr, Sacramento, CA 95817 USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Traumatol & Orthopaed, Dept Orthopaed,Sch Med,Shanghai Key Lab Prevent &, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yang, Kai,Li, Shunyao,Wang, Tianqi,et al. Development of an Orally Active Small-Molecule Inhibitor of Receptor Activator of Nuclear Factor-?B Ligand[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(16):10992-11009. |
| APA | Yang, Kai.,Li, Shunyao.,Wang, Tianqi.,Yan, Xueming.,He, Qian.,...&Deng, Lianfu.(2022).Development of an Orally Active Small-Molecule Inhibitor of Receptor Activator of Nuclear Factor-?B Ligand.JOURNAL OF MEDICINAL CHEMISTRY,65(16),10992-11009. |
| MLA | Yang, Kai,et al."Development of an Orally Active Small-Molecule Inhibitor of Receptor Activator of Nuclear Factor-?B Ligand".JOURNAL OF MEDICINAL CHEMISTRY 65.16(2022):10992-11009. |
入库方式： OAI收割
来源：上海药物研究所
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