• 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

针对糖原合酶激酶 3 的吡唑并三嗪的计算机辅助分子设计。

Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3.

机构信息

a Department of Chemical and Physical Biology , Centro de Investigaciones Biológicas (CIB, CSIC) Ramiro de Maeztu , Madrid , Spain.

b INFIQC- Department of Organic Chemistry, School of Chemical Sciences , National University of Córdoba , Córdoba , Argentine.

出版信息

J Enzyme Inhib Med Chem. 2019 Dec;34(1):87-96. doi: 10.1080/14756366.2018.1530223.

DOI:10.1080/14756366.2018.1530223
PMID:30362380
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6211276/
Abstract

Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer's disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1-3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood-brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD.

摘要

许多研究强调了糖原合酶激酶 3（GSK-3）在几种与阿尔茨海默病（AD）相关的过程中的意义。因此，GSK-3 已成为治疗这种神经退行性疾病的关键治疗靶点。在此，我们报告了乙基 4-氧代-吡唑并[4,3-d][1-3]三嗪-7-羧酸酯的设计和多步合成及其作为 GSK-3 抑制剂的生物学评价。分子建模研究使我们能够通过优化化学结构来开发这种新的支架。还描述了在酶中的潜在结合模式确定和催化部位的关键特征分析。此外，通过被动扩散评估了吡唑并三嗪酮穿过血脑屏障（BBB）的能力，并且那些显示出对 GSK-3 抑制和向中枢神经系统（CNS）渗透的吡唑并三嗪酮在基于细胞的模型中显示出对 tau 过度磷酸化的神经保护特性。这些新的可穿透大脑的吡唑并三嗪酮可用于关键的体内研究，并可被视为进一步优化治疗 AD 的新先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/135654579714/IENZ_A_1530223_F0009_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/f69dedfd90b4/IENZ_A_1530223_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/0a4f72390ef9/IENZ_A_1530223_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/cb1d8bd0c3a6/IENZ_A_1530223_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/ee4b49b4e211/IENZ_A_1530223_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/c2232703f9b9/IENZ_A_1530223_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/8496e61c34ca/IENZ_A_1530223_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/3b9721a5a7bc/IENZ_A_1530223_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/55f2bd825a5c/IENZ_A_1530223_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/ca2c15a1b610/IENZ_A_1530223_F0007_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/cfee2c531b5e/IENZ_A_1530223_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/135654579714/IENZ_A_1530223_F0009_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/f69dedfd90b4/IENZ_A_1530223_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/0a4f72390ef9/IENZ_A_1530223_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/cb1d8bd0c3a6/IENZ_A_1530223_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/ee4b49b4e211/IENZ_A_1530223_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/c2232703f9b9/IENZ_A_1530223_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/8496e61c34ca/IENZ_A_1530223_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/3b9721a5a7bc/IENZ_A_1530223_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/55f2bd825a5c/IENZ_A_1530223_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/ca2c15a1b610/IENZ_A_1530223_F0007_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/cfee2c531b5e/IENZ_A_1530223_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fa51/6211276/135654579714/IENZ_A_1530223_F0009_B.jpg

相似文献

1
Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3.针对糖原合酶激酶 3 的吡唑并三嗪的计算机辅助分子设计。
J Enzyme Inhib Med Chem. 2019 Dec;34(1):87-96. doi: 10.1080/14756366.2018.1530223.
2
Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer's disease.设计、合成并评价哈尔满衍生物作为潜在的 GSK-3β/DYRK1A 双重抑制剂用于治疗阿尔茨海默病。
Eur J Med Chem. 2021 Oct 15;222:113554. doi: 10.1016/j.ejmech.2021.113554. Epub 2021 May 29.
3
Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors.以 Tau 为中心的阿尔茨海默病多靶点方法：首创双糖原合酶激酶 3β 和 Tau 聚集抑制剂的开发。
J Med Chem. 2018 Sep 13;61(17):7640-7656. doi: 10.1021/acs.jmedchem.8b00610. Epub 2018 Aug 24.
4
Small molecules targeting glycogen synthase kinase 3 as potential drug candidates for the treatment of retinitis pigmentosa.靶向糖原合酶激酶3的小分子作为治疗视网膜色素变性的潜在候选药物。
J Enzyme Inhib Med Chem. 2017 Dec;32(1):522-526. doi: 10.1080/14756366.2016.1265522.
5
A Triazolotriazine-Based Dual GSK-3β/CK-1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition.基于三唑并三嗪的双重 GSK-3β/CK-1δ 配体，作为一种潜在的神经保护剂，呈现出两种不同的酶抑制机制。
ChemMedChem. 2019 Feb 5;14(3):310-314. doi: 10.1002/cmdc.201800778. Epub 2019 Jan 15.
6
Discovery of Selective, Substrate-Competitive, and Passive Membrane Permeable Glycogen Synthase Kinase-3β Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling of New C-Glycosylflavones.选择性、底物竞争性和被动膜渗透性糖原合成酶激酶-3β抑制剂的发现：新型 C-糖苷黄酮的合成、生物评价和分子模拟。
ACS Chem Neurosci. 2018 May 16;9(5):1166-1183. doi: 10.1021/acschemneuro.8b00010. Epub 2018 Feb 13.
7
Structure-based optimization of oxadiazole-based GSK-3 inhibitors.基于结构的恶二唑类糖原合成酶激酶-3抑制剂的优化
Eur J Med Chem. 2013 Mar;61:26-40. doi: 10.1016/j.ejmech.2012.06.006. Epub 2012 Jun 12.
8
Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as new glycogen synthase kinase-3β inhibitors.新型糖原合成酶激酶-3β抑制剂 1-苯基吡唑并[3,4-e]吡咯并[3,4-g]吲唑啉-4,6(1H,5H)-二酮的设计、合成与生物评价。
J Med Chem. 2013 Dec 27;56(24):10066-78. doi: 10.1021/jm401466v. Epub 2013 Dec 11.
9
SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tau hyperphosphorylation via down-regulating GSK-3β activity in SH-SY5Y cells.SLM，一种新型咔唑类荧光团，通过下调 SH-SY5Y 细胞中 GSK-3β 的活性来减弱冈田酸诱导的 tau 过度磷酸化。
Eur J Pharm Sci. 2017 Dec 15;110:101-108. doi: 10.1016/j.ejps.2017.03.037. Epub 2017 Mar 27.
10
Discovery of novel glycogen synthase kinase-3α inhibitors: Structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia.新型糖原合酶激酶-3α抑制剂的发现：基于结构的虚拟筛选、初步 SAR 及用于治疗急性髓性白血病的生物学评价。
Eur J Med Chem. 2019 Jun 1;171:221-234. doi: 10.1016/j.ejmech.2019.03.039. Epub 2019 Mar 20.

引用本文的文献

1
Synthesis, anticancer evaluation, and electrochemical investigation of new chiral pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides.新型手性吡唑并[4,3-e]四唑并[1,5-b][1,2,4]三嗪磺酰胺的合成、抗癌活性评价及电化学研究
Sci Rep. 2025 May 28;15(1):18640. doi: 10.1038/s41598-025-02835-w.
2
Novel synthesis of new triazine sulfonamides with antitumor, anti-microbial and anti-SARS-CoV-2 activities.具有抗肿瘤、抗菌和抗SARS-CoV-2活性的新型三嗪磺酰胺的合成
BMC Chem. 2024 Mar 26;18(1):58. doi: 10.1186/s13065-024-01164-9.
3
Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer's Disease.

本文引用的文献

1
Okadaic acid-induced tau hyperphosphorylation and the downregulation of Pin1 expression in primary cortical neurons.岗田酸诱导原代皮质神经元中的 tau 过度磷酸化和 Pin1 表达下调。
J Chem Neuroanat. 2018 Oct;92:41-47. doi: 10.1016/j.jchemneu.2018.05.006. Epub 2018 May 31.
2
SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tau hyperphosphorylation via down-regulating GSK-3β activity in SH-SY5Y cells.SLM，一种新型咔唑类荧光团，通过下调 SH-SY5Y 细胞中 GSK-3β 的活性来减弱冈田酸诱导的 tau 过度磷酸化。
Eur J Pharm Sci. 2017 Dec 15;110:101-108. doi: 10.1016/j.ejps.2017.03.037. Epub 2017 Mar 27.
3
糖原合成酶激酶-3β抑制剂的作用：阿尔茨海默病的新希望与机遇
Adv Pharm Bull. 2023 Nov;13(4):688-700. doi: 10.34172/apb.2023.071. Epub 2023 Jan 23.
4
Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches.通过计算方法研究绿原酸与 AMPA 受体相互作用的机制。
Molecules. 2022 May 25;27(11):3394. doi: 10.3390/molecules27113394.
5
Preparation of Novel Pyrazolo[4,3-]tetrazolo[1,5-][1,2,4]triazine Sulfonamides and Their Experimental and Computational Biological Studies.新型吡唑并[4,3-]四唑并[1,5-][1,2,4]三嗪磺酰胺的制备及其实验和计算生物学研究。
Int J Mol Sci. 2022 May 24;23(11):5892. doi: 10.3390/ijms23115892.
6
1,3,5-triazines inhibit osteosarcoma and avert lung metastasis in a patient-derived orthotopic xenograft mouse model with favorable pharmacokinetics.1,3,5-三嗪在具有良好药代动力学的患者来源原位异种移植小鼠模型中抑制骨肉瘤并防止肺转移。
Iran J Basic Med Sci. 2022 Mar;25(3):295-301. doi: 10.22038/IJBMS.2022.62705.13873.
Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease.
强效β-分泌酶1（BACE1）抑制剂的设计、合成及构效关系分析：阿尔茨海默病潜在的先导药物候选物
Eur J Med Chem. 2017 Jan 5;125:1213-1224. doi: 10.1016/j.ejmech.2016.11.021. Epub 2016 Nov 12.
4
Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors.作为磷脂酰肌醇4-激酶IIIβ抑制剂的嘌呤类似物。
Bioorg Med Chem Lett. 2016 Jun 1;26(11):2706-12. doi: 10.1016/j.bmcl.2016.04.002. Epub 2016 Apr 5.
5
Identifying Interactions that Determine Fragment Binding at Protein Hotspots.识别决定片段在蛋白质热点处结合的相互作用。
J Med Chem. 2016 May 12;59(9):4314-25. doi: 10.1021/acs.jmedchem.5b01980. Epub 2016 Apr 11.
6
Design, synthesis, and in vitro biological evaluation of novel 6-methyl-7-substituted-7-deaza purine nucleoside analogs as anti-influenza A agents.新型 6-甲基-7-取代-7-脱氮嘌呤核苷类似物的设计、合成及体外生物评价作为抗流感 A 药物。
Antiviral Res. 2016 May;129:13-20. doi: 10.1016/j.antiviral.2016.01.005. Epub 2016 Jan 21.
7
One-pot, three-component approach to the synthesis of 3,4,5-trisubstituted pyrazoles.一锅法、三组分合成3,4,5-三取代吡唑的方法。
J Org Chem. 2015 May 1;80(9):4325-35. doi: 10.1021/jo502946g. Epub 2015 Apr 17.
8
Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors.阿尔茨海默病的多靶标药物发现：三嗪酮作为 BACE-1 和 GSK-3β抑制剂。
Angew Chem Int Ed Engl. 2015 Jan 26;54(5):1578-82. doi: 10.1002/anie.201410456. Epub 2014 Dec 11.
9
Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases.糖原合酶激酶-3（GSK3）：调控、作用及相关疾病
Pharmacol Ther. 2015 Apr;148:114-31. doi: 10.1016/j.pharmthera.2014.11.016. Epub 2014 Nov 27.
10
Microwave-assisted preparation of 4-amino-3-cyano-5-methoxycarbonyl-N-arylpyrazoles as building blocks for the diversity-oriented synthesis of pyrazole-based polycyclic scaffolds.微波辅助制备4-氨基-3-氰基-5-甲氧基羰基-N-芳基吡唑作为用于基于吡唑的多环支架的多样性导向合成的构建模块。
Org Biomol Chem. 2015 Jan 14;13(2):409-23. doi: 10.1039/c4ob01951b. Epub 2014 Nov 4.