• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

氨基苯乙烯基苯并呋喃可直接减少淀粉样β寡聚体，并逆转阿尔茨海默病转基因小鼠的认知缺陷。

Aminostyrylbenzofuran directly reduces oligomeric amyloid-β and reverses cognitive deficits in Alzheimer transgenic mice.

作者信息

Lee Sang-Hyun, Kim YoungSoo, Kim Hye Yun, Kim Young Hoon, Kim Maeng Sup, Kong Jae Yang, Lee Mun-Han, Kim Dong Jin, Ahn Young Gil

机构信息

Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd., Hwaseong-si, Gyonggi-do, Republic of Korea; Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.

Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Biological Chemistry Program, University of Science and Technology (UST), Daejeon, Republic of Korea.

出版信息

PLoS One. 2014 Apr 23;9(4):e95733. doi: 10.1371/journal.pone.0095733. eCollection 2014.

DOI:10.1371/journal.pone.0095733
PMID:24760018
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3997483/
Abstract

Alzheimer's disease is an irreversible neurodegenerative disorder that is characterized by the abnormal aggregation of amyloid-β into neurotoxic oligomers and plaques. Although many disease-modifying molecules are currently in Alzheimer clinical trials, a small molecule that inhibits amyloid-β aggregation and ameliorates the disorder has not been approved to date. Herein, we report the effects of a potent small molecule, 6-methoxy-2-(4-dimethylaminostyryl) benzofuran (KMS88009), that directly disrupts amyloid-β oligomerization, preserving cognitive behavior when used prophylactically and reversing declines in cognitive behavior when used therapeutically. KMS88009 exhibited excellent pharmacokinetic profiles with extensive brain uptake and a high level of safety. When orally administered before and after the onset of Alzheimer's disease symptoms, KMS88009 significantly reduced assembly of amyloid-β oligomers and improved cognitive behaviors in the APP/PS1 double transgenic mouse model. The unique dual mode of action indicates that KMS88009 may be a powerful therapeutic candidate for the treatment of Alzheimer's disease.

摘要

阿尔茨海默病是一种不可逆的神经退行性疾病，其特征是β淀粉样蛋白异常聚集成神经毒性寡聚体和斑块。尽管目前许多疾病修饰分子正处于阿尔茨海默病临床试验阶段，但迄今为止，一种抑制β淀粉样蛋白聚集并改善该疾病的小分子药物尚未获批。在此，我们报告了一种强效小分子6-甲氧基-2-(4-二甲基氨基苯乙烯基)苯并呋喃(KMS88009)的作用，该小分子直接破坏β淀粉样蛋白的寡聚化，预防性使用时可保持认知行为，治疗性使用时可逆转认知行为的衰退。KMS88009表现出优异的药代动力学特征，具有广泛的脑摄取和高度的安全性。在阿尔茨海默病症状出现之前和之后口服给药时，KMS88009在APP/PS1双转基因小鼠模型中显著减少了β淀粉样蛋白寡聚体的组装并改善了认知行为。这种独特的双重作用模式表明，KMS88009可能是治疗阿尔茨海默病的有力候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/ceed600802d3/pone.0095733.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/9145f75a1134/pone.0095733.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/6ec403d4cf16/pone.0095733.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/8e52a1847441/pone.0095733.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/82d8144f55c7/pone.0095733.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/ceed600802d3/pone.0095733.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/9145f75a1134/pone.0095733.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/6ec403d4cf16/pone.0095733.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/8e52a1847441/pone.0095733.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/82d8144f55c7/pone.0095733.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9715/3997483/ceed600802d3/pone.0095733.g005.jpg

相似文献

1
Aminostyrylbenzofuran directly reduces oligomeric amyloid-β and reverses cognitive deficits in Alzheimer transgenic mice.氨基苯乙烯基苯并呋喃可直接减少淀粉样β寡聚体，并逆转阿尔茨海默病转基因小鼠的认知缺陷。
PLoS One. 2014 Apr 23;9(4):e95733. doi: 10.1371/journal.pone.0095733. eCollection 2014.
2
L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer's disease.L-3-正丁基苯酞可改善阿尔茨海默病转基因模型的认知障碍并减少淀粉样β。
J Neurosci. 2010 Jun 16;30(24):8180-9. doi: 10.1523/JNEUROSCI.0340-10.2010.
3
WBQ5187, a Multitarget Directed Agent, Ameliorates Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease and Modulates Cerebral β-Amyloid, Gliosis, cAMP Levels, and Neurodegeneration.WBQ5187，一种多靶点导向剂，可改善阿尔茨海默病转基因小鼠模型的认知障碍，并调节脑内β-淀粉样蛋白、神经胶质增生、cAMP 水平和神经退行性变。
ACS Chem Neurosci. 2019 Dec 18;10(12):4787-4799. doi: 10.1021/acschemneuro.9b00409. Epub 2019 Nov 20.
4
A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S )-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease.一种新型糖原合酶激酶-3 抑制剂 2-甲基-5-(3-{4-[(S)-甲基亚磺酰基]苯基}-1-苯并呋喃-5-基)-1,3,4-恶二唑可降低 tau 磷酸化并改善阿尔茨海默病转基因模型的认知缺陷。
J Neurochem. 2011 Dec;119(6):1330-40. doi: 10.1111/j.1471-4159.2011.07532.x. Epub 2011 Nov 2.
5
Orally Administered Benzofuran Derivative Disaggregated Aβ Plaques and Oligomers in the Brain of 5XFAD Alzheimer Transgenic Mouse.口服苯并呋喃衍生物可使 5XFAD 阿尔茨海默病转基因小鼠大脑中的 Aβ斑块和寡聚体解聚。
ACS Chem Neurosci. 2021 Jan 6;12(1):99-108. doi: 10.1021/acschemneuro.0c00606. Epub 2020 Dec 17.
6
L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer's transgenic mice.L-3-正丁基苯酞可降低 tau 磷酸化水平，改善 APP/PS1 阿尔茨海默病转基因小鼠的认知功能障碍。
J Alzheimers Dis. 2012;29(2):379-91. doi: 10.3233/JAD-2011-111577.
7
Cerebral inoculation of human A53T α-synuclein reduces spatial memory decline and amyloid-β aggregation in APP/PS1 transgenic mice of Alzheimer's disease.脑内接种人 A53T α-突触核蛋白可减少阿尔茨海默病 APP/PS1 转基因小鼠的空间记忆下降和淀粉样β聚集。
Brain Res Bull. 2018 Oct;143:116-122. doi: 10.1016/j.brainresbull.2018.10.003. Epub 2018 Oct 24.
8
Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer's disease mouse model.提高大脑中的镁含量可预防阿尔茨海默病小鼠模型中的突触损失并逆转认知缺陷。
Mol Brain. 2014 Sep 13;7:65. doi: 10.1186/s13041-014-0065-y.
9
Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing Aβ deposition.华佗再造丸通过改善突触可塑性和减少 Aβ 沉积改善 APP/PS1 转基因小鼠的认知障碍。
BMC Complement Altern Med. 2018 May 29;18(1):167. doi: 10.1186/s12906-018-2237-2.
10
Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer's Disease.大规模口服治疗研究，使用四种最有前途的 D3 衍生物治疗阿尔茨海默病。
Molecules. 2017 Oct 10;22(10):1693. doi: 10.3390/molecules22101693.

引用本文的文献

1
Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of β-amyloid peptide.通过加速β-淀粉样肽聚集来挽救 APP/PS1 小鼠的认知缺陷。
Alzheimers Res Ther. 2019 Dec 17;11(1):106. doi: 10.1186/s13195-019-0560-6.
2
A small molecule Nec-1 directly induces amyloid clearance in the brains of aged APP/PS1 mice.一种小分子 Nec-1 可直接诱导老年 APP/PS1 小鼠大脑中的淀粉样蛋白清除。
Sci Rep. 2019 Mar 12;9(1):4183. doi: 10.1038/s41598-019-40205-5.
3
QIAD assay for quantitating a compound's efficacy in elimination of toxic Aβ oligomers.

本文引用的文献

1
Preventing Alzheimer's disease.预防阿尔茨海默病。
Science. 2012 Sep 21;337(6101):1488-92. doi: 10.1126/science.1228541.
2
Immunotherapy for Alzheimer disease: the challenge of adverse effects.阿尔茨海默病的免疫疗法：不良反应的挑战。
Nat Rev Neurol. 2012 Aug;8(8):465-9. doi: 10.1038/nrneurol.2012.118. Epub 2012 Jul 3.
3
Alzheimer mechanisms and therapeutic strategies.阿尔茨海默病的发病机制与治疗策略。
用于定量化合物清除有毒Aβ寡聚体功效的QIAD检测法。
Sci Rep. 2015 Sep 23;5:13222. doi: 10.1038/srep13222.
4
Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.淀粉样β寡聚体在阿尔茨海默病发病机制、治疗及诊断中的作用
Acta Neuropathol. 2015 Feb;129(2):183-206. doi: 10.1007/s00401-015-1386-3. Epub 2015 Jan 22.
5
A common control group - optimising the experiment design to maximise sensitivity.一个共同的对照组——优化实验设计以最大化灵敏度。
PLoS One. 2014 Dec 11;9(12):e114872. doi: 10.1371/journal.pone.0114872. eCollection 2014.
Cell. 2012 Mar 16;148(6):1204-22. doi: 10.1016/j.cell.2012.02.040.
4
New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs.治疗阿尔茨海默病的新药理学策略：关注疾病修饰药物。
Br J Clin Pharmacol. 2012 Apr;73(4):504-17. doi: 10.1111/j.1365-2125.2011.04134.x.
5
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.阿尔茨海默病的淀粉样蛋白级联假说：治疗药物开发的评估。
Nat Rev Drug Discov. 2011 Aug 19;10(9):698-712. doi: 10.1038/nrd3505.
6
Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.淀粉样β寡聚体以依赖钙调神经磷酸酶的方式损害小鼠的恐惧条件记忆。
J Neurosci Res. 2010 Oct;88(13):2923-32. doi: 10.1002/jnr.22445.
7
Alzheimer's disease: strategies for disease modification.阿尔茨海默病：疾病修饰策略。
Nat Rev Drug Discov. 2010 May;9(5):387-98. doi: 10.1038/nrd2896.
8
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.阿尔茨海默病病理级联的动态生物标志物假设模型。
Lancet Neurol. 2010 Jan;9(1):119-28. doi: 10.1016/S1474-4422(09)70299-6.
9
Frequent amyloid deposition without significant cognitive impairment among the elderly.老年人中频繁出现淀粉样蛋白沉积但无明显认知障碍。
Arch Neurol. 2008 Nov;65(11):1509-17. doi: 10.1001/archneur.65.11.1509.
10
Aminostyrylbenzofuran derivatives as potent inhibitors for Abeta fibril formation.氨基苯乙烯基苯并呋喃衍生物作为β-淀粉样蛋白原纤维形成的有效抑制剂。
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5591-3. doi: 10.1016/j.bmcl.2008.08.111. Epub 2008 Sep 3.