Discovery and Evaluation of Enantiopure 9 H -pyrimido[4,5- b ]indoles as Nanomolar GSK-3β Inhibitors with Improved Metabolic Stability.

Autor: Andreev S; Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Pantsar T; 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., El-Gokha A; Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.; Chemistry Department, Faculty of Science, Menoufia University, Gamal Abdel-Nasser Street, Shebin El-Kom 32511, Egypt., Ansideri F; Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Kudolo M; Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Anton DB; Cell Culture Laboratory, Postgraduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado 95914-014, Brazil., Sita G; Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy., Romasco J; Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso D'Augusto, 237, 47921 Rimini, Italy., Geibel C; Institute of Pharmaceutical Sciences, Department of Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Lämmerhofer M; Institute of Pharmaceutical Sciences, Department of Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Goettert MI; Cell Culture Laboratory, Postgraduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado 95914-014, Brazil., Tarozzi A; Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso D'Augusto, 237, 47921 Rimini, Italy., Laufer SA; Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Koch P; Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.; Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2020 Oct 22; Vol. 21 (21). Date of Electronic Publication: 2020 Oct 22.
DOI: 10.3390/ijms21217823
Abstrakt: 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 H -pyrimido[4,5- b ]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9 H -pyrimido[4,5- b ]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile ( 1 ) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1 , 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, ( R )-3-(3-((7-chloro-9 H -pyrimido[4,5- b ]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ( (R) -2 ) and ( R )-1-(3-((7-bromo-9 H pyrimido[4,5- b ]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ( (R) -28 ), exhibited IC 50 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.
Databáze: MEDLINE
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