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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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Original languageEnglish
Pages140-152
Number of pages13
JournalJournal of Medicinal Chemistry
Journal publication date12 Jan 2012
Volume55
Issue1
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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    Reprinted with permission from Brand, S, Cleghorn, LAT, McElroy, SP, Robinson, DA, Smith, VC, Hallyburton, I, Harrison, JR, Norcross, NR, Spinks, D, Bayliss, T, Norval, S, Stojanovski, L, Torrie, LS, Frearson, JA, Brenk, R, Fairlamb, AH, Ferguson, MAJ, Read, KD, Wyatt, PG & Gilbert, IH 2012, 'Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors' Journal of Medicinal Chemistry, vol 55, no. 1, pp. 140-152.. Copyright 2012 American Chemical Society.

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