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Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease

文献类型：期刊论文

作者Zhou, Jianhui6,7; Wang, Ning4,5; Wang, Mengxue3,6,7; Hu, Yuting3,6,7; Zhang, Zhenwei1,3,6; Gu, Zhiyong1,2,3; Wang, Jing3,6,7; Shou, Haowen3,6; Cheng, Xi1,2,3; Liu, Hong1,2,3,6,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-06-03
卷号67期号:11页码:8836-8861
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00159
通讯作者Liu, Hong(hliu@simm.ac.cn) ; Li, Yang(oceanyangli@fudan.edu.cn) ; Zhou, Yu(zhouyu@simm.ac.cn)
英文摘要More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound LH2-051 with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for LH2-051, and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of A beta aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds 37 and 45 are promising preclinical drug candidates for the treatment of AD.
WOS关键词AUTOPHAGY ; CASCADE ; DESIGN ; MEMORY
资助项目Innovative Research Team of High-level Local University in Shanghai[82173656] ; Innovative Research Team of High-level Local University in Shanghai[82373709] ; Innovative Research Team of High-level Local University in Shanghai[92057103] ; Innovative Research Team of High-level Local University in Shanghai[31872820] ; National Natural Science Foundation of China[2022ZD0213000] ; Ministry of Science and Technology of the People's Republic of China[23XD1420800] ; Program of Shanghai Academic/Technology Research Leader[23ZR1479400] ; Shanghai 2023 Science and Technology Innovation Action Plan Natural Science Foundation Original Exploration Project ; Innovative Research Team of High-Level Local Universities in Shanghai[ZDSYS14005] ; Key Laboratory Program of the Education Commission of Shanghai Municipality[SIMM2004KF-09] ; State Key Laboratory of Drug Research
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001238294900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/311779]  
专题新药研究国家重点实验室
通讯作者Liu, Hong; Li, Yang; Zhou, Yu
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Fudan Univ, Sch Basic Med Sci, Minist Educ, MOE Frontiers Ctr Brain Sci,Key Lab Metab & Mol Me, Shanghai 200032, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol,State Key Lab Med Neurobiol, Minist Educ, Shanghai 200032, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Jianhui,Wang, Ning,Wang, Mengxue,et al. Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(11):8836-8861.
APA Zhou, Jianhui.,Wang, Ning.,Wang, Mengxue.,Hu, Yuting.,Zhang, Zhenwei.,...&Zhou, Yu.(2024).Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease.JOURNAL OF MEDICINAL CHEMISTRY,67(11),8836-8861.
MLA Zhou, Jianhui,et al."Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease".JOURNAL OF MEDICINAL CHEMISTRY 67.11(2024):8836-8861.

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来源：上海药物研究所

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