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

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

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Authors

  • 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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Info

Original languageEnglish
Pages140-152
Number of pages13
JournalJournal of Medicinal Chemistry
Journal publication date12 Jan 2012
Journal number1
Volume55
DOIs
StatePublished

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.

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