The design and synthesis of potent and selective inhibitors of trypanosoma brucei glycogen synthase kinase 3 for the treatment of human African trypanosomiasis

Robert Urich, Raffaella Grimaldi, Torsten Luksch, Julie A. Frearson, Ruth Brenk (Lead / Corresponding author), Paul G. Wyatt (Lead / Corresponding author)

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    22 Citations (Scopus)

    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 GSK3ß enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.

    Original languageEnglish
    Pages (from-to)7536-7549
    Number of pages14
    JournalJournal of Medicinal Chemistry
    Volume57
    Issue number18
    DOIs
    Publication statusPublished - 25 Sep 2014

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