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Glycogen synthase kinase-3&#946; (GSK-3&#946;) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer&#8217;s disease. We herein report on the optimization of a novel class of GSK-3&#946; 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>]indole-based derivatives and studied their structure&#8722;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-(3a<i>RS</i>,7a<i>SR</i>)-(1-(7-chloro-9<i>H</i>-pyrimido[4,5-<i>b</i>]indol-4-yl)octahydro-6<i>H</i>-pyrrolo[2,3-<i>c</i>]pyridin-6-yl)-propanenitrile (<b>24</b>), which displayed an IC₅₀ value of 130 nM on GSK-3&#946; 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&#946; by 1 &#181;s molecular dynamics simulations.