• 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

相似文献

1
Discovery of PIPE-359, a Brain-Penetrant, Selective M Receptor Antagonist with Robust Efficacy in Murine MOG-EAE.PIPE-359的发现，一种具有脑渗透性的选择性M受体拮抗剂，在小鼠MOG-EAE模型中具有强大疗效。
ACS Med Chem Lett. 2020 Dec 24;12(1):155-161. doi: 10.1021/acsmedchemlett.0c00626. eCollection 2021 Jan 14.
2
Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model.髓鞘少突胶质细胞糖蛋白（MOG）诱导实验性自身免疫性脑脊髓炎（EAE）模型的滴定。
J Neurosci Methods. 2021 Mar 1;351:108999. doi: 10.1016/j.jneumeth.2020.108999. Epub 2020 Nov 12.
3
T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis.实验性自身免疫性脑脊髓炎和多发性硬化中T细胞和B细胞对髓鞘少突胶质细胞糖蛋白的反应
Glia. 2001 Nov;36(2):220-34. doi: 10.1002/glia.1111.
4
Analysis of gene expression in MOG-induced experimental autoimmune encephalomyelitis after treatment with a novel brain-penetrating antioxidant.新型脑渗透性抗氧化剂治疗后MOG诱导的实验性自身免疫性脑脊髓炎中的基因表达分析
J Mol Neurosci. 2005;27(1):125-35. doi: 10.1385/JMN:27:1:125.
5
Gene Expression in Spontaneous Experimental Autoimmune Encephalomyelitis Is Linked to Human Multiple Sclerosis Risk Genes.自发性实验性自身免疫性脑脊髓炎中的基因表达与人类多发性硬化症风险基因相关。
Front Immunol. 2020 Sep 18;11:2165. doi: 10.3389/fimmu.2020.02165. eCollection 2020.
6
Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein.抗原特异性抗体在重组髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎中的关键作用
Eur J Immunol. 2002 Jul;32(7):1905-13. doi: 10.1002/1521-4141(200207)32:7<1905::AID-IMMU1905>3.0.CO;2-L.
7
Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M(1) and M(4) muscarinic acetylcholine receptors agonists.二氢喹唑啉酮衍生物作为强效、选择性且可穿透中枢神经系统的M(1)和M(4)毒蕈碱型乙酰胆碱受体激动剂的发现。
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5357-61. doi: 10.1016/j.bmcl.2015.09.032. Epub 2015 Sep 12.
8
The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease.多发性硬化症中针对髓鞘少突胶质细胞糖蛋白（MOG）的自身免疫反应具有潜在致病性：共聚物1对MOG诱导疾病的影响。
J Neurol. 1996 Apr;243(4 Suppl 1):S14-22. doi: 10.1007/BF00873697.
9
Cathepsin C modulates myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.组织蛋白酶 C 调节髓鞘少突胶质糖蛋白诱导的实验性自身免疫性脑脊髓炎。
J Neurochem. 2019 Feb;148(3):413-425. doi: 10.1111/jnc.14581. Epub 2018 Dec 3.
10
Novel Zebrafish EAE model: A quick in vivo screen for multiple sclerosis.新型斑马鱼实验性自身免疫性脑脊髓炎模型：用于多发性硬化症的快速体内筛选
Mult Scler Relat Disord. 2017 Jan;11:32-39. doi: 10.1016/j.msard.2016.11.010. Epub 2016 Nov 28.

引用本文的文献

1
The potential of repurposing clemastine to promote remyelination.重新利用氯马斯汀促进髓鞘再生的潜力。
Front Cell Neurosci. 2025 May 7;19:1582902. doi: 10.3389/fncel.2025.1582902. eCollection 2025.
2
Enhancing remyelination in multiple sclerosis via M1 muscarinic acetylcholine receptor.通过M1毒蕈碱型乙酰胆碱受体增强多发性硬化症的髓鞘再生
Mol Pharmacol. 2025 Apr;107(4):100027. doi: 10.1016/j.molpha.2025.100027. Epub 2025 Feb 28.
3
Design, Synthesis, and Biological Evaluation of 4,4'-Difluorobenzhydrol Carbamates as Selective M Antagonists.4,4'-二氟二苯甲醇氨基甲酸酯类作为选择性M拮抗剂的设计、合成及生物学评价
Pharmaceuticals (Basel). 2022 Feb 18;15(2):248. doi: 10.3390/ph15020248.
4
Potential Role for Combined Subtype-Selective Targeting of M and M Muscarinic Receptors in Gastrointestinal and Liver Diseases.M 型和 M 型毒蕈碱受体联合亚型选择性靶向在胃肠道和肝脏疾病中的潜在作用
Front Pharmacol. 2021 Nov 4;12:786105. doi: 10.3389/fphar.2021.786105. eCollection 2021.

本文引用的文献

1
Advances in the Treatment of Multiple Sclerosis.多发性硬化症的治疗进展。
Neurol Clin. 2021 Feb;39(1):21-33. doi: 10.1016/j.ncl.2020.09.002. Epub 2020 Nov 7.
2
Structure and selectivity engineering of the M muscarinic receptor toxin complex.M 毒蕈碱型乙酰胆碱受体毒素复合物的结构与选择性工程改造。
Science. 2020 Jul 10;369(6500):161-167. doi: 10.1126/science.aax2517.
3
Tuning Properties for Blood-Brain Barrier Permeation: A Statistics-Based Analysis.调节血脑屏障通透性的特性：基于统计学的分析。
ACS Chem Neurosci. 2020 Jan 2;11(1):34-44. doi: 10.1021/acschemneuro.9b00541. Epub 2019 Dec 18.
4
The Blood-Brain Barrier (BBB) Score.血脑屏障（BBB）评分。
J Med Chem. 2019 Nov 14;62(21):9824-9836. doi: 10.1021/acs.jmedchem.9b01220. Epub 2019 Oct 25.
5
Immunological Aspects of Approved MS Therapeutics.已获批多发性硬化症治疗药物的免疫学方面。
Front Immunol. 2019 Jul 11;10:1564. doi: 10.3389/fimmu.2019.01564. eCollection 2019.
6
Developing therapeutic strategies to promote myelin repair in multiple sclerosis.制定促进多发性硬化症髓鞘修复的治疗策略。
Expert Rev Neurother. 2019 Oct;19(10):997-1013. doi: 10.1080/14737175.2019.1632192. Epub 2019 Jun 20.
7
Validation of Human MDR1-MDCK and BCRP-MDCK Cell Lines to Improve the Prediction of Brain Penetration.验证人 MDR1-MDCK 和 BCRP-MDCK 细胞系以提高对脑穿透的预测。
J Pharm Sci. 2019 Jul;108(7):2476-2483. doi: 10.1016/j.xphs.2019.02.005. Epub 2019 Feb 20.
8
The prevalence of MS in the United States: A population-based estimate using health claims data.美国多发性硬化症的患病率：基于健康索赔数据的人群估计。
Neurology. 2019 Mar 5;92(10):e1029-e1040. doi: 10.1212/WNL.0000000000007035. Epub 2019 Feb 15.
9
Autoradiography of H-pirenzepine and H-AFDX-384 in Mouse Brain Regions: Possible Insights into M, M, and M Muscarinic Receptors Distribution.小鼠脑区中H-哌仑西平和H-AFDX-384的放射自显影：对M1、M2和M3毒蕈碱受体分布的可能见解。
Front Pharmacol. 2018 Feb 20;9:124. doi: 10.3389/fphar.2018.00124. eCollection 2018.
10
Multiple Sclerosis: Mechanisms of Disease and Strategies for Myelin and Axonal Repair.多发性硬化症：疾病机制以及髓鞘和轴突修复策略
Neurol Clin. 2018 Feb;36(1):1-11. doi: 10.1016/j.ncl.2017.08.002.

PIPE-359的发现，一种具有脑渗透性的选择性M受体拮抗剂，在小鼠MOG-EAE模型中具有强大疗效。

Discovery of PIPE-359, a Brain-Penetrant, Selective M Receptor Antagonist with Robust Efficacy in Murine MOG-EAE.

作者信息

Schrader Thomas O, Xiong Yifeng, Lorenzana Ariana O, Broadhead Alexander, Stebbins Karin J, Poon Michael M, Baccei Christopher, Lorrain Daniel S

机构信息

Pipeline Therapeutics, 10578 Science Center Drive, Suite 200, San Diego, California 92121, United States.

出版信息

ACS Med Chem Lett. 2020 Dec 24;12(1):155-161. doi: 10.1021/acsmedchemlett.0c00626. eCollection 2021 Jan 14.

DOI:10.1021/acsmedchemlett.0c00626
PMID:33488977
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7812680/
Abstract

The discovery of PIPE-359, a brain-penetrant and selective antagonist of the muscarinic acetylcholine receptor subtype 1 is described. Starting from a literature-reported M antagonist, linker replacement and structure-activity relationship investigations of the eastern 1-(pyridinyl)piperazine led to the identification of a novel, potent, and selective antagonist with good MDCKII-MDR1 permeability. Continued semi-iterative positional scanning facilitated improvements in the metabolic and hERG profiles, which ultimately delivered PIPE-359. This advanced drug candidate exhibited robust efficacy in mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE), a preclinical model for multiple sclerosis.

摘要

本文描述了1型毒蕈碱型乙酰胆碱受体的脑渗透性选择性拮抗剂PIPE-359的发现过程。从文献报道的M拮抗剂出发，通过连接基团替换以及对1-(吡啶基)哌嗪东侧进行构效关系研究，鉴定出一种新型、强效且具有选择性的拮抗剂，其在MDCKII-MDR1模型中具有良好的通透性。持续进行的半迭代位置扫描促进了代谢和hERG特性的改善，最终得到了PIPE-359。这种先进的候选药物在小鼠髓鞘少突胶质细胞糖蛋白(MOG)诱导的实验性自身免疫性脑脊髓炎(EAE，一种多发性硬化症的临床前模型)中显示出强大的疗效。