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Open AccessArticle

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

1
Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
2
Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Str. 14, 72076 Tübingen, Germany
3
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
4
Department of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55099 Mainz, Germany
5
Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Christian Peifer
Molecules 2019, 24(12), 2331; https://doi.org/10.3390/molecules24122331
Received: 23 May 2019 / Revised: 19 June 2019 / Accepted: 20 June 2019 / Published: 25 June 2019
(This article belongs to the Special Issue Kinase Inhibitors II)
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-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]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-(3aRS,7aSR)-(1-(7-chloro-9H-pyrimido[4,5-b]indol-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-propanenitrile (24), which displayed an IC50 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. View Full-Text
Keywords: Glycogen synthase kinase-3β; 7-chloro-9H-pyrimido[4,5-b]indole; protein kinase; kinase inhibitor; tofacitinib Glycogen synthase kinase-3β; 7-chloro-9H-pyrimido[4,5-b]indole; protein kinase; kinase inhibitor; tofacitinib
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Andreev, S.; Pantsar, T.; Ansideri, F.; Kudolo, M.; Forster, M.; Schollmeyer, D.; Laufer, S.A.; Koch, P. Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors. Molecules 2019, 24, 2331.

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