Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease
Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC50 = 0.049 μmol/L, huBuChE IC50 = 0.066 μmol/L...
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| Language: | English |
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Elsevier
2025-04-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525001078 |
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| author | Zhipei Sang Shuheng Huang Wanying Tan Yujuan Ban Keren Wang Yufan Fan Hongsong Chen Qiyao Zhang Chanchan Liang Jing Mi Yunqi Gao Ya Zhang Wenmin Liu Jianta Wang Wu Dong Zhenghuai Tan Lei Tang Haibin Luo |
| author_facet | Zhipei Sang Shuheng Huang Wanying Tan Yujuan Ban Keren Wang Yufan Fan Hongsong Chen Qiyao Zhang Chanchan Liang Jing Mi Yunqi Gao Ya Zhang Wenmin Liu Jianta Wang Wu Dong Zhenghuai Tan Lei Tang Haibin Luo |
| author_sort | Zhipei Sang |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC50 = 0.049 μmol/L, huBuChE IC50 = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood–brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications. |
| format | Article |
| id | doaj-art-e5147979d02b44c2bd6b95f9df92f331 |
| institution | OA Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-e5147979d02b44c2bd6b95f9df92f3312025-08-20T01:49:04ZengElsevierActa Pharmaceutica Sinica B2211-38352025-04-011542134215510.1016/j.apsb.2025.02.030Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's diseaseZhipei Sang0Shuheng Huang1Wanying Tan2Yujuan Ban3Keren Wang4Yufan Fan5Hongsong Chen6Qiyao Zhang7Chanchan Liang8Jing Mi9Yunqi Gao10Ya Zhang11Wenmin Liu12Jianta Wang13Wu Dong14Zhenghuai Tan15Lei Tang16Haibin Luo17State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China; Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, ChinaCenter of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, ChinaCollege of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, ChinaShanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaCollege of Animal Science and Technology Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, ChinaCollege of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, ChinaCollege of Animal Science and Technology Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, ChinaShanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaCollege of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, ChinaState Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, ChinaCollege of Animal Science and Technology Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, China; Corresponding authors.Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China; Corresponding authors.State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China; Corresponding authors.Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, ChinaAlzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC50 = 0.049 μmol/L, huBuChE IC50 = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood–brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.http://www.sciencedirect.com/science/article/pii/S2211383525001078Alzheimer's diseaseSelective BuChE inhibitorPharmacokinetic studiesPharmacodynamic studiesMechanism of action |
| spellingShingle | Zhipei Sang Shuheng Huang Wanying Tan Yujuan Ban Keren Wang Yufan Fan Hongsong Chen Qiyao Zhang Chanchan Liang Jing Mi Yunqi Gao Ya Zhang Wenmin Liu Jianta Wang Wu Dong Zhenghuai Tan Lei Tang Haibin Luo Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease Acta Pharmaceutica Sinica B Alzheimer's disease Selective BuChE inhibitor Pharmacokinetic studies Pharmacodynamic studies Mechanism of action |
| title | Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease |
| title_full | Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease |
| title_fullStr | Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease |
| title_full_unstemmed | Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease |
| title_short | Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease |
| title_sort | discovery of novel butyrylcholinesterase inhibitors for treating alzheimer s disease |
| topic | Alzheimer's disease Selective BuChE inhibitor Pharmacokinetic studies Pharmacodynamic studies Mechanism of action |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525001078 |
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