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

Chao Zhang; Lan Wang; Yixiang Xu; Yunyuan Huang; Junyang Huang; Jin Zhu; Wei Wang; Wangsheng Li; Annan Sun; Xiaokang Li; Haiyan Zhang; Jian Li

doi:10.1016/j.ejmech.2022.114347

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

Eur J Med Chem. 2022 Jun 5:236:114347. doi: 10.1016/j.ejmech.2022.114347. Epub 2022 Apr 6.

Authors

Chao Zhang¹, Lan Wang², Yixiang Xu¹, Yunyuan Huang¹, Junyang Huang¹, Jin Zhu¹, Wei Wang³, Wangsheng Li³, Annan Sun⁴, Xiaokang Li⁵, Haiyan Zhang⁶, Jian Li⁷

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China.
⁴ College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
⁵ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China. Electronic address: xkli@ecust.edu.cn.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China. Electronic address: hzhang@simm.ac.cn.
⁷ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China; Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, 5 Xue Ren Road, Dali, 671000, Yunnan, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China; Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou, 570228, Hainan, China. Electronic address: jianli@ecust.edu.cn.

PMID: 35430560
DOI: 10.1016/j.ejmech.2022.114347

Abstract

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 μM) 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 Aβ_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.

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

MeSH terms

Aged
Alzheimer Disease* / drug therapy
Comorbidity
Depression / drug therapy
Drug Design
Humans
Prospective Studies
Receptor for Advanced Glycation End Products / therapeutic use

Substances

Receptor for Advanced Glycation End Products