The design and synthesis of potent and selective inhibitors of Trypanosoma brucei glycogen synthase kinase 3 for the treatment of human african trypanosomiasis.

J Med Chem 2014 Sep 8;57(18):7536-49. Epub 2014 Sep 8.

Drug Discovery Unit, College of Life Sciences, University of Dundee , Sir James Black Centre, Dow Street, Dundee DD1 5EH, U.K.

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.

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http://dx.doi.org/10.1021/jm500239bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175002PMC
September 2014
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