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

被引：94

作者：

Brand, Stephen ^{[1
]}

Cleghorn, Laura A. T. ^{[1
]}

McElroy, Stuart P. ^{[1
]}

Robinson, David A. ^{[1
]}

Smith, Victoria C. ^{[1
]}

Hallyburton, Irene ^{[1
]}

Harrison, Justin R. ^{[1
]}

Norcross, Neil R. ^{[1
]}

Spinks, Daniel ^{[1
]}

Bayliss, Tracy ^{[1
]}

Norval, Suzanne ^{[1
]}

Stojanovski, Laste ^{[1
]}

Torrie, Leah S. ^{[1
]}

Frearson, Julie A. ^{[1
]}

Brenk, Ruth ^{[1
]}

Fairlamb, Alan H. ^{[1
]}

Ferguson, Michael A. J. ^{[1
]}

Read, Kevin D. ^{[1
]}

Wyatt, Paul G. ^{[1
]}

Gilbert, Ian H. ^{[1
]}

机构：

[1] Univ Dundee, Drug Discovery Unit, Div Biol Chem & Drug Discovery, Coll Life Sci,Sir James Black Ctr, Dundee DD1 5EH, Scotland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 01期

基金：

英国惠康基金;

关键词：

CANDIDA-ALBICANS; TRYPANOSOMA-BRUCEI; DRUG DISCOVERY; PEPTIDOMIMETIC INHIBITORS; SELECTIVE INHIBITORS; DIPEPTIDE AMIDES; PROTEIN; DESIGN; POTENT; BENZOFURANS;

D O I：

10.1021/jm201091t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

收藏

页码：140 / 152

页数：13

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