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 (IC 50 = 2 nM) and T. brucei (EC 50 = 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. © 2011 American Chemical Society.
CITATION STYLE
Brand, S., Cleghorn, L. A. T., McElroy, S. P., Robinson, D. A., Smith, V. C., Hallyburton, I., … Gilbert, I. H. (2012). Discovery of a novel class of orally active trypanocidal N-Myristoyltransferase inhibitors. Journal of Medicinal Chemistry, 55(1), 140–152. https://doi.org/10.1021/jm201091t
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