Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-04-22 DOI:10.1016/j.ejmech.2025.117678

Barbora Svobodova , Zuzana Moravcova , Anna Misiachna , Gabriela Novakova , Ales Marek , Vladimir Finger , Jitka Odvarkova , Jaroslav Pejchal , Jana Zdarova Karasova , Jakub Netolicky , Marek Ladislav , Martina Hrabinova , Ales Sorf , Lubica Muckova , Lenka Fikejzlova , Marketa Benkova , Martin Novak , Lukas Prchal , Jan Capek , Jiri Handl , Jan Korabecny

{"title":"Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment","authors":"Barbora Svobodova , Zuzana Moravcova , Anna Misiachna , Gabriela Novakova , Ales Marek , Vladimir Finger , Jitka Odvarkova , Jaroslav Pejchal , Jana Zdarova Karasova , Jakub Netolicky , Marek Ladislav , Martina Hrabinova , Ales Sorf , Lubica Muckova , Lenka Fikejzlova , Marketa Benkova , Martin Novak , Lukas Prchal , Jan Capek , Jiri Handl , Jan Korabecny","doi":"10.1016/j.ejmech.2025.117678","DOIUrl":null,"url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117678"},"PeriodicalIF":6.0000,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S022352342500443X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.

Abstract Image

查看原文本刊更多论文

基于他克林的新型多靶点定向配体：增强胆碱酯酶抑制、NMDA 受体拮抗和中枢神经系统生物利用度以治疗阿尔茨海默病

阿尔茨海默病（AD）是一种多发性神经退行性疾病，目前的治疗方法主要通过抑制胆碱酯酶（ChE）和拮抗 N-甲基-D-天冬氨酸受体（NMDAR）来缓解症状。为了提高疗效和安全性，我们设计并合成了 16 种新型他克林衍生物，这些衍生物的第 7 位被各种（杂）芳基或氘取代。最初，我们通过硅学筛选预测了其良好的中枢神经系统渗透性和口服生物利用度。随后进行的体外评估表明，它对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）具有显著的抑制作用，其中衍生物 5i 和 5m 的抑制作用尤为突出。利用人体肝脏微粒体进行的代谢稳定性评估显示，化合物 5e 的稳定性有所提高，而 5i 和 5m 的代谢速度较快。值得注意的是，化合物 7 由于掺入了氘而显示出更高的代谢稳定性。进一步测试了新合成化合物对 NMDAR 的 GluN1/GluN2B 亚型的拮抗活性，其中化合物 5m 的抑制作用最强，且与电压无关。体外 PAMPA 试验证实了这些化合物渗透血脑屏障（BBB）的能力。在初步肝毒性筛选（HepG2 细胞）中，大多数衍生物表现出比他克林更高的细胞毒性，突显了肝毒性管理方面的持续挑战。基于其总体良好的特征，化合物 5m 进入了小鼠体内药代动力学研究，显示出高效的中枢神经系统穿透性，脑浓度超过血浆水平（脑-血浆比为 2.36），表明其通过 BBB 的转运活跃。这些研究结果突出表明，化合物 5m 是一种很有前景的基于他克林的多靶点定向配体，支持进一步进行临床前开发，以作为治疗注意力缺失症的潜在候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.