☆ 4.7 Article

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

JOURNAL OF MEDICINAL CHEMISTRY (2012)

期刊

JOURNAL OF MEDICINAL CHEMISTRY

卷 55, 期 1, 页码 140-152

出版社

AMER CHEMICAL SOC

DOI: 10.1021/jm201091t

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Chemistry, Medicinal

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Wellcome Trust [WT077705, WT083481, WT085622]

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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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