ChemInform Abstract: Design, Synthesis and Biological Evaluation of Benzothiazepinones (BTZs) as Novel Non-ATP Competitive Inhibitors of Glycogen Synthase Kinase-3β (GSK-3β).

ChemInform ◽  
2013 ◽  
Vol 44 (27) ◽  
pp. no-no
Author(s):  
Peng Zhang ◽  
Hai-Rong Hu ◽  
Shi-Hui Bian ◽  
Zhao-Hui Huang ◽  
Yong Chu ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Biological Evaluation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Design Synthesis ◽  
Competitive Inhibitors ◽  
Gsk 3Β ◽  
Synthesis And Biological Evaluation

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

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2331 ◽  
Author(s):  
Stanislav Andreev ◽  
Tatu Pantsar ◽  
Francesco Ansideri ◽  
Mark Kudolo ◽  
Michael Forster ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Biological Evaluation ◽  
Glycogen Synthase Kinase ◽  
Binding Modes ◽  
Glycogen Synthase Kinase 3Β ◽  
Design Synthesis ◽  
Atp Binding Site ◽  
Ic50 Value ◽  
Gsk 3Β ◽  
Dynamics Simulations

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,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-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.

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