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


ABSTRACT: Glycogen synthase kinase-3? (GSK-3?) 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-3? 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-3? 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.

SUBMITTER: Andreev S 

PROVIDER: S-EPMC7659979 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Andreev Stanislav S   Pantsar Tatu T   El-Gokha Ahmed A   Ansideri Francesco F   Kudolo Mark M   Anton Débora Bublitz DB   Sita Giulia G   Romasco Jenny J   Geibel Christian C   Lämmerhofer Michael M   Goettert Márcia Ines MI   Tarozzi Andrea A   Laufer Stefan A SA   Koch Pierre P  

International journal of molecular sciences 20201022 21


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<i>H</i>-pyrimido[4,5-<i>b</i>]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9<i>H</i>-pyrimido[4,5-<i>b</i>]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (<b>1</b>) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from <b>1</b>, we prepared a series  ...[more]

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