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.
J Med Chem. 2012 Jan 12;55(1):140-52. doi: 10.1021/jm201091t. Epub 2011 Dec 7.
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.
N-豆蔻酰转移酶（NMT）是一种很有前途的药物靶点，可用于治疗由寄生虫原生动物布氏锥虫引起的非洲人类锥虫病（HAT）。我们报告了高内涵筛选命中物（1）的优化，得到了先导分子 DDD85646（63），它对酶（IC50=2 nM）和培养中的布氏锥虫（EC50=2 nM）具有很强的活性。该化合物具有良好的口服药代动力学特性，并能治愈啮齿动物外周 HAT 感染模型。该化合物为验证布氏锥虫 NMT 作为 HAT 的药物靶点提供了一个极好的工具，同时也是进一步优化的有价值的先导化合物。
