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Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors
[Image: see text] 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...
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2011
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256935/ https://www.ncbi.nlm.nih.gov/pubmed/22148754 http://dx.doi.org/10.1021/jm201091t |
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| author | 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. |
| author_facet | 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. |
| author_sort | Brand, Stephen |
| collection | PubMed |
| description | [Image: see text] 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. |
| format | Online Article Text |
| id | pubmed-3256935 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2011 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-32569352012-01-12 Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors 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. J Med Chem [Image: see text] 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. American Chemical Society 2011-12-07 2012-01-12 /pmc/articles/PMC3256935/ /pubmed/22148754 http://dx.doi.org/10.1021/jm201091t Text en Copyright © 2011 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
| spellingShingle | 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. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors |
| title | Discovery of a Novel Class
of Orally Active Trypanocidal N-Myristoyltransferase
Inhibitors |
| title_full | Discovery of a Novel Class
of Orally Active Trypanocidal N-Myristoyltransferase
Inhibitors |
| title_fullStr | Discovery of a Novel Class
of Orally Active Trypanocidal N-Myristoyltransferase
Inhibitors |
| title_full_unstemmed | Discovery of a Novel Class
of Orally Active Trypanocidal N-Myristoyltransferase
Inhibitors |
| title_short | Discovery of a Novel Class
of Orally Active Trypanocidal N-Myristoyltransferase
Inhibitors |
| title_sort | discovery of a novel class
of orally active trypanocidal n-myristoyltransferase
inhibitors |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256935/ https://www.ncbi.nlm.nih.gov/pubmed/22148754 http://dx.doi.org/10.1021/jm201091t |
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