Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors.
Molecules. 2019 Jun 25; 24(12)M

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-((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.

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Authors+Show Affiliations

Andreev S

Pantsar T

Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Str. 14, 72076 Tübingen, Germany. tatu.pantsar@uef.fi. School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. tatu.pantsar@uef.fi.

Department of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55099 Mainz, Germany. scholli@uni-mainz.de.

Laufer SA

Koch P

Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. pierre.koch@uni-tuebingen.de. Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstraβe 31, 93053 Regensburg, Germany. pierre.koch@uni-tuebingen.de.

MeSH

Adenosine TriphosphateBinding SitesChemistry Techniques, SyntheticDose-Response Relationship, DrugDrug DesignEnzyme ActivationEnzyme InhibitorsGlycogen Synthase Kinase 3 betaHumansHydrophobic and Hydrophilic InteractionsMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureProtein BindingProtein Kinase InhibitorsStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31242571

Citation

Andreev, Stanislav, et al. "Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors." Molecules (Basel, Switzerland), vol. 24, no. 12, 2019.

Andreev S, Pantsar T, Ansideri F, et al. Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors. Molecules. 2019;24(12).

Andreev, S., Pantsar, T., Ansideri, F., Kudolo, M., Forster, M., Schollmeyer, D., Laufer, S. A., & Koch, P. (2019). Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors. Molecules (Basel, Switzerland), 24(12). https://doi.org/10.3390/molecules24122331

Andreev S, et al. Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors. Molecules. 2019 Jun 25;24(12) PubMed PMID: 31242571.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors. AU - Andreev,Stanislav, AU - Pantsar,Tatu, AU - Ansideri,Francesco, AU - Kudolo,Mark, AU - Forster,Michael, AU - Schollmeyer,Dieter, AU - Laufer,Stefan A, AU - Koch,Pierre, Y1 - 2019/06/25/ PY - 2019/05/23/received PY - 2019/06/19/revised PY - 2019/06/20/accepted PY - 2019/6/28/entrez PY - 2019/6/28/pubmed PY - 2019/12/18/medline KW - 7-chloro-9H-pyrimido[4,5-b]indole KW - Glycogen synthase kinase-3β KW - kinase inhibitor KW - protein kinase KW - tofacitinib JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 12 N2 - 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. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/31242571/Design_Synthesis_and_Biological_Evaluation_of_7_Chloro_9H_pyrimido[45_b]indole_based_Glycogen_Synthase_Kinase_3β_Inhibitors_ DB - PRIME DP - Unbound Medicine ER -

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Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors.Molecules. 2019 Jun 25; 24(12)M