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

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-((3,4)-3-((7-chloro-9-pyrimido[4,5-]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (). We synthesized a series of 19 novel 7-chloro-9-pyrimido[4,5-]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-(3a,7a)-(1-(7-chloro-9-pyrimido[4,5-]indol-4-yl)octahydro-6-pyrrolo[2,3-]pyridin-6-yl)-propanenitrile (), which displayed an IC 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.