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

ABSTRACT: 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-((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,7a

SUBMITTER: Andreev S 

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

REPOSITORIES: biostudies-literature