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7-氯-9-嘧啶并[4,5-]吲哚基糖原合酶激酶-3β抑制剂的设计、合成与生物评价。

Design, Synthesis and Biological Evaluation of 7-Chloro-9-pyrimido[4,5-]indole-based Glycogen Synthase Kinase-3β Inhibitors.

机构信息

Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.

Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Str. 14, 72076 Tübingen, Germany.

出版信息

Molecules. 2019 Jun 25;24(12):2331. doi: 10.3390/molecules24122331.

DOI:10.3390/molecules24122331
PMID:31242571
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6630214/
Abstract

Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer's disease. We herein report on the optimization of a novel class of GSK-3β inhibitors based on the tofacitinib-derived screen hit 3-((3,4)-3-((7-chloro-9-pyrimido[4,5-]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (). We synthesized a series of 19 novel 7-chloro-9-pyrimido[4,5-]indole-based derivatives and studied their structure-activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successful rigidization approach afforded 3-(3a,7a)-(1-(7-chloro-9-pyrimido[4,5-]indol-4-yl)octahydro-6-pyrrolo[2,3-]pyridin-6-yl)-propanenitrile (), which displayed an IC value of 130 nM on GSK-3β and was further characterized by its metabolic stability. Finally, we disclosed the putative binding modes of the most potent inhibitors within the ATP binding site of GSK-3β by 1 µs molecular dynamics simulations.

摘要

糖原合酶激酶-3β（GSK-3β）是治疗包括阿尔茨海默病在内的神经退行性疾病的重要药物靶点。我们在此报告了基于托法替尼衍生的筛选命中物 3-((3,4)-3-((7-氯-9-嘧啶并[4,5-]吲哚-4-基)(甲基)氨基)-4-甲基哌啶-1-基)-3-氧代丙腈（）的新型 GSK-3β 抑制剂的优化。我们合成了一系列 19 种新型 7-氯-9-嘧啶并[4,5-]吲哚类衍生物，并研究了它们的结构-活性关系，重点是氰乙酰基哌啶部分。我们揭示了氰基的关键作用及其对该化合物系列活性的重要性。成功的刚性化方法得到了 3-(3a,7a)-(1-(7-氯-9-嘧啶并[4,5-]吲哚-4-基)八氢-6-吡咯并[2,3-]吡啶-6-基)-丙腈（），其对 GSK-3β 的 IC 值为 130 nM，并且具有更好的代谢稳定性。最后，我们通过 1 µs 分子动力学模拟揭示了最有效抑制剂在 GSK-3β 的 ATP 结合位点中的可能结合模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/367c8af00d48/molecules-24-02331-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/43ae0754c935/molecules-24-02331-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/0ab3b8c3945d/molecules-24-02331-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/651049331bc1/molecules-24-02331-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/e12ea033ee45/molecules-24-02331-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/10fba1f15597/molecules-24-02331-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/fedba8ccb5ce/molecules-24-02331-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/bb235bd54658/molecules-24-02331-sch004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/da06c3428e58/molecules-24-02331-sch005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/a238549c554c/molecules-24-02331-sch006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/367c8af00d48/molecules-24-02331-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/43ae0754c935/molecules-24-02331-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/0ab3b8c3945d/molecules-24-02331-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/651049331bc1/molecules-24-02331-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/e12ea033ee45/molecules-24-02331-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/10fba1f15597/molecules-24-02331-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/fedba8ccb5ce/molecules-24-02331-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/bb235bd54658/molecules-24-02331-sch004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/da06c3428e58/molecules-24-02331-sch005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/a238549c554c/molecules-24-02331-sch006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e5e/6630214/367c8af00d48/molecules-24-02331-g004.jpg

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