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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：140-152
• 全文大小：715K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

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.