Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Stephen Brand, Laura A. T. Cleghorn, Stuart P. McElroy, David A. Robinson, Victoria C. Smith, Irene Hallyburton, Justin R. Harrison, Neil R. Norcross, Daniel Spinks, Tracy Bayliss, Suzanne Norval, Laste Stojanovski, Leah S. Torrie, Julie A. Frearson, Ruth Brenk, Alan H. Fairlamb, Michael A. J. Ferguson, Kevin D. Read, Paul G. Wyatt, Ian H. Gilbert (Lead / Corresponding author)

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    Abstract

    N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

    Original languageEnglish
    Pages (from-to)140-152
    Number of pages13
    JournalJournal of Medicinal Chemistry
    Volume55
    Issue number1
    DOIs
    Publication statusPublished - 12 Jan 2012

    Keywords

    • CANDIDA-ALBICANS
    • TRYPANOSOMA-BRUCEI
    • DRUG DISCOVERY
    • PEPTIDOMIMETIC INHIBITORS
    • SELECTIVE INHIBITORS
    • DIPEPTIDE AMIDES
    • PROTEIN
    • DESIGN
    • POTENT
    • BENZOFURANS

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