Department of Chemistry, University of Sheffield, Brook Hill, UK.
ChemMedChem. 2011 Jan 3;6(1):115-30. doi: 10.1002/cmdc.201000383.
Structure-activity relationships within the indole-3-glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC₅₀ <10 nM). After examining a range of substituents at the para-position of the N-phenylglyoxylamide moiety, five-membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie-infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole-3-glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.
进一步探索了吲哚-3-基乙二酰亚胺类抗朊病毒试剂的构效关系，发现了几种新化合物，在朊病毒病的细胞系模型中表现出优异的活性（EC₅₀<10 nM）。在研究了 N-苯乙二酰亚胺部分对位的一系列取代基后，发现至少含有两个杂原子的五元杂环对于抗朊病毒作用是最佳的。对该乙二酰亚胺亚结构的重要性进行了一些修饰，但没有一种能很好地耐受。然而，最有效的化合物对微粒体代谢的稳定性确实很大，最活跃的文库成员在单次治疗后可无限期治愈感染羊瘙痒病的细胞。目前的结果证实，吲哚-3-基乙二酰亚胺是一种很有前途的先导系列化合物，可继续在体外和体内进行抗朊病毒病的评估。
