Abstract
Glycogen synthase kinase 3 (GSK3) is a genetically validated drug target for human African trypanosomiasis (HAT), also called African sleeping sickness. We report the synthesis and biological evaluation of aminopyrazole derivatives as Trypanosoma brucei GSK3 short inhibitors. Low nanomolar inhibitors, which had high selectivity over the off-target human CDK2 and good selectivity over human GSK3β enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Binding Sites
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Chemistry Techniques, Synthetic
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Cyclin-Dependent Kinase 2 / chemistry
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Cyclin-Dependent Kinase 2 / metabolism
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Drug Design*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Humans
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Models, Molecular
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Protein Conformation
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrazoles / therapeutic use
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Substrate Specificity
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Trypanosomiasis, African / drug therapy*
Substances
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Enzyme Inhibitors
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Pyrazoles
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pyrazole
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Adenosine Triphosphate
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Cyclin-Dependent Kinase 2
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Glycogen Synthase Kinase 3