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

ABSTRACT: Glycogen synthase kinase-3? (GSK-3?) 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-3? 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-3? 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-3? by 1 µs molecular dynamics simulations.

SUBMITTER: Andreev S 

PROVIDER: S-EPMC6630214 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Andreev Stanislav S   Pantsar Tatu T   Ansideri Francesco F   Kudolo Mark M   Forster Michael M   Schollmeyer Dieter D   Laufer Stefan A SA   Koch Pierre P  

Molecules (Basel, Switzerland) 20190625 12

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-((3<i>R</i>,4<i>R</i>)-3-((7-chloro-9<i>H</i>-pyrimido[4,5-<i>b</i>]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (<b>1</b>). We synthesized a series of 19 novel 7-chloro-9<i>H</i>-pyrimido[4,5-<i>b</i>  ...[more]

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