Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression
Discovery of novel dual RAGE/SERT inhibitors for the potential treatment of the comorbidity of Alzheimer's disease and depression
复制标题
发现新型 RAGE/SERT 双重抑制剂，可用于治疗阿尔茨海默病和抑郁症的共病
DOI：
10.1016/j.ejmech.2022.114347
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发表时间：
2022
影响因子：
6.7
通讯作者：
Jian Li
中科院分区：
文献类型：
--
作者：
Chao Zhang;Lan Wang;Yixiang Xu;Yunyuan Huang;Junyang Huang;Jin Zhu;Wei Wang;Wangsheng Li;Annan Sun;Xiaokang Li;Haiyan Zhang;Jian Li
抑郁症被认为是阿尔茨海默病（AD）最常见的精神症状之一。阿尔茨海默病与抑郁症的合并症增加了老年患者临床治疗和护理的负担。为了寻找新的治疗方案，我们首先通过融合维拉唑酮和阿泽拉贡的关键药效，提出了RAGE/SERT双抑制剂，用于治疗AD合并抑郁的潜在治疗。经过一系列的结构修饰，设计合成了34个双靶点定向配体，并对其RAGE和SERT抑制活性进行了系统评价。其中，化合物12体外抗RAGE （IC50= 8.26±1.12 μM）和SERT （IC50= 31.09±5.15 nM）具有良好的双靶点生物活性，安全性优于阿塞利agon，具有良好的肝微粒体稳定性、较弱的CYP抑制作用和良好的药代动力学特性。此外，12能改善a - β25-35诱导的SH-SY5Y细胞的神经毒性，缓解尾悬试验中的抑郁症状。总之，这些结果表明，12是潜在的治疗阿尔茨海默病伴抑郁的潜在原型。
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, compound12showed 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,12ameliorated Aβ25-35-induced neurotoxicity in SH-SY5Y cells and alleviated the depressive symptom in tail suspension test. In brief, these results indicated that12is a prospective prototype for the potential treatment of AD with comorbid depression.