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

作者：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^*

来源：Journal of Medicinal Chemistry, 2012, 55(1): 140-152.

DOI：10.1021/jm201091t

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.

• 出版日期2012-1-12