Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression
文献类型：期刊论文
| 作者 | Zhang, Chao7; Wang, Lan2,6; Xu, Yixiang7; Huang, Yunyuan7; Huang, Junyang7; Zhu, Jin7; Wang, Wei6; Li, Wangsheng6; Sun, Annan1; Li, Xiaokang7 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-06-05 |
| 卷号 | 236页码:17 |
| 关键词 | Alzheimer's disease
Depression
Multi-target-directed ligands
RAGE (Receptor for advanced glycation end & nbsp SERT (Serotonin transporter) products) |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2022.114347 |
| 通讯作者 | Li, Xiaokang(xkli@ecust.edu.cn) ; Zhang, Haiyan(hzhang@simm.ac.cn) ; Li, Jian(jianli@ecust.edu.cn) |
| 英文摘要 | Depression is identified as one of the most common psychiatric symptoms in Alzheimer's disease (AD). The comorbidity of AD and depression increases the burden of clinical treatment and care in elderly patients. In order to find new treatment options, we first proposed the dual RAGE/SERT inhibitors by fusing the key pharmacophore of vilazodone and azeliragon for the potential treatment of AD with comorbid depression. After a series of structural modifications, 34 dual-target directed ligands were designed and synthesized, and their RAGE and SERT inhibitory activities were systematically evaluated. Among them, compound 12 showed good dual-target bioactivities against RAGE (IC50 = 8.26 +/- 1.12 mM) and SERT (IC50 = 31.09 +/- 5.15 nM) in vitro, better safety profile than azeliragon, good liver microsomal stability, weak CYP inhibition, and acceptable pharmacokinetic properties. Moreover, 12 ameliorated A beta(25-35)-induced neurotoxicity in SH-SY5Y cells and alleviated the depressive symptom in tail suspension test. In brief, these results indicated that 12 is a prospective prototype for the potential treatment of AD with comorbid depression. (C) 2022 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | SEROTONIN REUPTAKE INHIBITORS ; END-PRODUCTS ; RECEPTOR ; RAGE ; DEMENTIA ; NEUROTOXICITY ; MECHANISMS ; RISK |
| 资助项目 | National Natural Science Foundation of China[81903457] ; National Natural Science Foundation of China[81872747] ; National Natural Science Foundation of China[31972169] ; National Natural Science Foundation of China[22037002] ; National Natural Science Foundation of China[22107030] ; Shanghai Sailing Program[19YF1412600] ; Shanghai Morning Light Program[18CG33] ; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism ; Innovative Research Team of Highlevel Local Universities in Shanghai ; Chinese Special Fund for State Key Laboratory of Bioreactor Engineering[2060204] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000793653100001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/301071]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Xiaokang; Zhang, Haiyan; Li, Jian |
| 作者单位 | 1.Univ N Carolina, Coll Arts & Sci, Chapel Hill, NC 27514 USA 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Hainan, Peoples R China 4.Tongji Univ, Shanghai Peoples Hosp 10, Clin Med Sci & Tech Innovat Ctr, Sch Med, Shanghai 200092, Peoples R China 5.Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, 5 Xue Ren Rd, Dali 671000, Yunnan, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd,Zhanidiang Hitech Pk, Shanghai 201203, Peoples R China 7.East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Me, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm,State Key Lab Bioreactor Engn, 130 Mei Long Rd, Shanghai 200237, Peoples R China |
| 推荐引用方式 GB/T 7714 |
Zhang, Chao,Wang, Lan,Xu, Yixiang,et al. Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,236:17. |
| APA |
Zhang, Chao.,Wang, Lan.,Xu, Yixiang.,Huang, Yunyuan.,Huang, Junyang.,...&Li, Jian.(2022). Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression .EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,236,17. |
| MLA |
Zhang, Chao,et al." Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression ".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 236(2022):17. |
入库方式： OAI收割
来源：上海药物研究所
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