Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease
文献类型：期刊论文
| 作者 | Mao, Fei2; Wang, Huan3,4; Ni, Wei2; Zheng, Xinyu2; Wang, Manjiong2; Bao, Keting2; Ling, Dazheng2; Li, Xiaokang2; Xu, Yixiang2; Zhang, Haiyan1,3
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| 刊名 | ACS CHEMICAL NEUROSCIENCE
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| 出版日期 | 2018-02 |
| 卷号 | 9期号:2页码:328-345 |
| 关键词 | Alzheimer's disease drug repositioning dual-target inhibitor AChE inhibition PDE5 inhibition |
| ISSN号 | 1948-7193 |
| DOI | 10.1021/acschemneuro.7b00345 |
| 文献子类 | Article |
| 英文摘要 | Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDES inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w.Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDESA confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo. |
| WOS关键词 | AMYLOID-BETA AGGREGATION ; CHOLINESTERASE/MONOAMINE OXIDASE-INHIBITORS ; DIAPOPHYTOENE DESATURASE CRTN ; MULTITARGET-DIRECTED LIGANDS ; APP/PS1 TRANSGENIC MICE ; AUREUS MRSA INFECTIONS ; BLOOD-BRAIN-BARRIER ; LONG-TERM-MEMORY ; MOUSE MODEL ; COGNITIVE FUNCTION |
| 资助项目 | National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[21672064] ; National Natural Science Foundation of China[81522045] ; Shanghai Sailing Program[17YF1403600] ; Shanghai Education Development Foundation[14SG28] ; Fundamental Research Funds for the Central Universities[00000000] ; Shanghai Municipal Education Commission[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000426144000024 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279921]  |
| 专题 | 药理学第二研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Haiyan; Li, Jian |
| 作者单位 | 1.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Mao, Fei,Wang, Huan,Ni, Wei,et al. Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease[J]. ACS CHEMICAL NEUROSCIENCE,2018,9(2):328-345. |
| APA | Mao, Fei.,Wang, Huan.,Ni, Wei.,Zheng, Xinyu.,Wang, Manjiong.,...&Li, Jian.(2018).Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease.ACS CHEMICAL NEUROSCIENCE,9(2),328-345. |
| MLA | Mao, Fei,et al."Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease".ACS CHEMICAL NEUROSCIENCE 9.2(2018):328-345. |
入库方式： OAI收割
来源：上海药物研究所
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