Discovery of a Novel Class of Orally Active Trypanocidal <i>N</i>-Myristoyltransferase Inhibitors
Stephen Brand(Discovery Centre), Laura A. T. Cleghorn(Discovery Centre), Stuart P. McElroy(Discovery Centre), David A. Robinson(Discovery Centre), Victoria Smith(Discovery Centre), Irene Hallyburton(Discovery Centre), Justin R. Harrison(Discovery Centre), Neil R. Norcross(Discovery Centre), Daniel Spinks(Discovery Centre), Tracy Bayliss(Discovery Centre), Suzanne Norval(Discovery Centre), Laste Stojanovski(Discovery Centre), Leah S. Torrie(Discovery Centre), Julie A. Frearson(Discovery Centre), Ruth Brenk(Discovery Centre), Alan H. Fairlamb(Discovery Centre), Michael A. J. Ferguson(Discovery Centre), Kevin D. Read(Discovery Centre), Paul G. Wyatt(Discovery Centre), Ian H. Gilbert(Discovery Centre)
Cited by 115Open Access
Abstract
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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