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

[Image: see text] 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...

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Detalles Bibliográficos
Autores principales: Brand, Stephen, Cleghorn, Laura A. T., McElroy, Stuart P., Robinson, David A., Smith, Victoria C., Hallyburton, Irene, Harrison, Justin R., Norcross, Neil R., Spinks, Daniel, Bayliss, Tracy, Norval, Suzanne, Stojanovski, Laste, Torrie, Leah S., Frearson, Julie A., Brenk, Ruth, Fairlamb, Alan H., Ferguson, Michael A. J., Read, Kevin D., Wyatt, Paul G., Gilbert, Ian H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2011
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256935/
https://www.ncbi.nlm.nih.gov/pubmed/22148754
http://dx.doi.org/10.1021/jm201091t
Descripción
Sumario:[Image: see text] 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.

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