Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.

J Med Chem 2012 Jan 7;55(1):140-52. Epub 2011 Dec 7.

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, U.K.

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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Source
http://pubs.acs.org/doi/10.1021/jm201091t
Publisher Site
http://dx.doi.org/10.1021/jm201091tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256935PMC
January 2012
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