文献类型：期刊文献

英文题名：Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression

作者：Zhang, Chao[1];Wang, Lan[2,6];Xu, Yixiang[1];Huang, Yunyuan[1];Huang, Junyang[1];Zhu, Jin[1];Wang, Wei[2];Li, Wangsheng[2];Sun, Annan[7];Li, Xiaokang[1];Zhang, Haiyan[2];Li, Jian[1,3,4,5]

机构：[1]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;[2]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;[3]Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, 5 Xue Ren Rd, Dali 671000, Yunnan, Peoples R China;[4]Tongji Univ, Shanghai Peoples Hosp 10, Clin Med Sci & Tech Innovat Ctr, Sch Med, Shanghai 200092, Peoples R China;[5]Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Hainan, Peoples R China;[6]Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;[7]Univ N Carolina, Coll Arts & Sci, Chapel Hill, NC 27514 USA

年份：2022

卷号：236

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000793653100001)】；

基金：This work was supported by the National Natural Science Foundation of China (81903457, 81872747, 31972169, 22037002, 22107030), the Shanghai Sailing Program (19YF1412600), and the Shanghai Morning Light Program (18CG33), the Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03e28), the Innovative Research Team of Highlevel Local Universities in Shanghai, the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204).

语种：英文

外文关键词：Alzheimer's disease; Depression; Multi-target-directed ligands; RAGE (Receptor for advanced glycation end products); SERT (Serotonin transporter)

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.