Stanislav Andreev1, Tatu Pantsar1,2, Ahmed El-Gokha1,3, Francesco Ansideri1, Mark Kudolo1, Débora Bublitz Anton4, Giulia Sita5, Jenny Romasco6, Christian Geibel7, Michael Lämmerhofer7, Márcia Ines Goettert4, Andrea Tarozzi6, Stefan A Laufer1, Pierre Koch1,8. 1. Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. 2. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. 3. Chemistry Department, Faculty of Science, Menoufia University, Gamal Abdel-Nasser Street, Shebin El-Kom 32511, Egypt. 4. Cell Culture Laboratory, Postgraduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado 95914-014, Brazil. 5. Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy. 6. Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso D'Augusto, 237, 47921 Rimini, Italy. 7. Institute of Pharmaceutical Sciences, Department of Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. 8. Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany.
Abstract
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 9H-pyrimido[4,5-b]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9H-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-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 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.
Glycogen synthase kinase-3β (GSK-3β) is a potential target in the field of class="Disease">Alzheimer's disease drug discovery. We recently reported a class="Chemical">new class of n class="Chemical">9H-pyrimido[4,5-b]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9H-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-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 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.
Authors: Georg Wuitschik; Erick M Carreira; Björn Wagner; Holger Fischer; Isabelle Parrilla; Franz Schuler; Mark Rogers-Evans; Klaus Müller Journal: J Med Chem Date: 2010-04-22 Impact factor: 7.446
Authors: Matthias Gehringer; Michael Forster; Ellen Pfaffenrot; Silke M Bauer; Stefan A Laufer Journal: ChemMedChem Date: 2014-08-19 Impact factor: 3.466