Title |
Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors
|
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Published in |
Journal of Medicinal Chemistry, December 2011
|
DOI | 10.1021/jm201091t |
Pubmed ID | |
Authors |
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 |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | <1% |
India | 1 | <1% |
Argentina | 1 | <1% |
Brazil | 1 | <1% |
Unknown | 108 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 27 | 24% |
Student > Ph. D. Student | 25 | 22% |
Student > Bachelor | 11 | 10% |
Student > Master | 9 | 8% |
Professor | 5 | 4% |
Other | 18 | 16% |
Unknown | 17 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 43 | 38% |
Agricultural and Biological Sciences | 22 | 20% |
Pharmacology, Toxicology and Pharmaceutical Science | 10 | 9% |
Biochemistry, Genetics and Molecular Biology | 8 | 7% |
Medicine and Dentistry | 3 | 3% |
Other | 7 | 6% |
Unknown | 19 | 17% |