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


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.

DOI: 10.1021/jm201091t

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@inproceedings{Brand2012DiscoveryOA, title={Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors}, author={Stephen Brand and Laura A. T. Cleghorn and Stuart P. McElroy and David A. Robinson and Victoria Smith and Irene Hallyburton and Justin R. Harrison and Neil R. Norcross and Daniel Spinks and Tracy Bayliss and Suzanne Norval and Laste Stojanovski and Leah S. Torrie and Julie A. Frearson and Ruth Brenk and Alan H. Fairlamb and Michael A. J. Ferguson and Kevin D. Read and Paul G Wyatt and Ian H. Gilbert}, booktitle={Journal of medicinal chemistry}, year={2012} }