Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Int J Mol Sci. 2020 Oct 22;21(21):7823. doi: 10.3390/ijms21217823.
Glycogen synthase kinase-3β (GSK-3β) is a potential target in the field of Alzheimer's disease drug discovery. We recently reported a new class of 9-pyrimido[4,5-]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9-pyrimido[4,5-]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile () demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from , we prepared a series of amide-based derivatives and studied their structure-activity relationships against GSK-3β supported by 1 µs molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, ()-3-(3-((7-chloro-9-pyrimido[4,5-]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile () and ()-1-(3-((7-bromo-9pyrimido[4,5-]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one (), exhibited IC values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties.
糖原合酶激酶-3β（GSK-3β）是阿尔茨海默病药物发现领域的一个潜在靶点。我们最近报道了一类新的 9-嘧啶并[4,5-e]吲哚为基础的 GSK-3β抑制剂，其中 3-（3-（（7-氯-9-嘧啶并[4,5-e]吲哚-4-基）（甲基）氨基）哌啶-1-基）丙腈（）表现出有希望的抑制活性。然而，该化合物在人肝微粒体中迅速降解。从开始，我们制备了一系列酰胺类衍生物，并通过 1 µs 分子动力学模拟研究了它们对 GSK-3β的构效关系。通过确定手性中心的优势构象，该系列化合物的生物活性得到了显著提高。此外，酰胺键的引入被证明是消除代谢热点的有效策略。最有效的化合物（）-3-（3-（（7-氯-9-嘧啶并[4,5-e]吲哚-4-基）（甲基）氨基）哌啶-1-基）-3-氧代丙腈（）和（）-1-（3-（（7-溴-9-嘧啶并[4,5-e]吲哚-4-基）（甲基）氨基）哌啶-1-基）-1-丙酮（），其 IC 值分别为 480 nM 和 360 nM，且显示出改善的代谢稳定性。它们具有最小的细胞毒性和神经保护特性，这进一步补充了它们良好的生物学特性。
