Li Zhe, Gever Joel, Rao Satish, Widjaja Kartika, Prusiner Stanley B, Silber B Michael
Institute for Neurodegenerative Diseases, University of California, San Francisco, California ; Department of Neurology, University of California, San Francisco, California.
ACS Med Chem Lett. 2013 Apr 11;4(4):397-401. doi: 10.1021/ml300472n.
Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) and kuru in humans, BSE in cattle, and scrapie in sheep. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrP) of a normally benign, host cellular protein, denoted PrP. We employed high-throughput screening (HTS) ELISAs to evaluate compounds for their ability to reduce the level of PrP in Rocky Mountain Laboratory (RML) prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as , , , and , displayed moderate antiprion activity with EC values in the micromolar range. Key analogs were designed and synthesized based on the SAR, with analogs , , , and found to have sub-micromolar potency. Analogs and were able to penetrate the blood-brain barrier (BBB) and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.
朊病毒疾病是一组致命的神经退行性疾病，包括人类的克雅氏病（CJD）和库鲁病、牛的疯牛病以及羊的瘙痒病。此类疾病是由一种正常情况下无害的宿主细胞蛋白（称为PrPC）的错误折叠致病异构体（称为PrPsc）的转化和积累所引起的。我们采用高通量筛选（HTS）酶联免疫吸附测定法来评估化合物降低落基山实验室（RML）朊病毒感染的小鼠神经母细胞瘤细胞（ScN2a-cl3）中PrP水平的能力。芳基哌嗪是所鉴定出的活性化合物之一，但最初筛选出的化合物效力低且类药性质差。其中表现最佳的化合物（如 、 、 和 ）显示出中等的抗朊病毒活性，其半数有效浓度（EC）值在微摩尔范围内。基于构效关系设计并合成了关键类似物，发现类似物 、 、 和 具有亚微摩尔效力。类似物 和 能够穿透血脑屏障（BBB），口服给药后在小鼠脑中达到了优异的药物浓度。这些化合物是我们在寻找治疗朊病毒疾病潜在候选药物的进一步先导优化中的良好起点。
