Li Zhe, Rao Satish, Gever Joel R, 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 ; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California.
ACS Med Chem Lett. 2013 Jul 11;4(7):647-650. doi: 10.1021/ml300454k.
The prion diseases caused by PrP, an alternatively folded form of the cellular prion protein (PrP), are rapidly progressive, fatal, and untreatable neurodegenerative syndromes. We employed HTS ELISA assays to identify compounds that lower the level of PrP in prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. SAR studies indicated that small amides with one aromatic, or heteroaromatic ring, on each side of the amide bond are of modest potency. Of note, benzamide (), with an EC of 2200 nM, was one of only a few arylamide hits with a piperazine group on its aniline moiety. The basic piperazine nitrogen can be protonated at physiologic pH, improving solubility, and therefore we wanted to exploit this feature in our search for a drug candidate. An SAR campaign resulted in several key analogs, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogs have submicromolar potency, with the most potent analog having an EC = 22 nM. More importantly, and several biarylamides (, , , ) were able to traverse the BBB and displayed excellent drug levels in the brains of mice following oral dosing. These biarylamides may represent good starting points for further lead optimization for the identification of potential drug candidates for the treatment of prion diseases.
由细胞朊蛋白（PrP）的一种可变折叠形式PrP引起的朊病毒疾病是快速进展、致命且无法治疗的神经退行性综合征。我们采用高通量筛选酶联免疫吸附测定（HTS ELISA）来鉴定可降低朊病毒感染的小鼠神经母细胞瘤（ScN2a-cl3）细胞中PrP水平的化合物，并鉴定出了一系列芳基酰胺。构效关系（SAR）研究表明，酰胺键两侧各带有一个芳环或杂芳环的小酰胺具有中等活性。值得注意的是，苯甲酰胺（），其半数有效浓度（EC）为2200 nM，是苯胺部分带有哌嗪基团的少数几种芳基酰胺活性化合物之一。碱性的哌嗪氮在生理pH下可质子化，从而提高溶解度，因此我们希望在寻找候选药物时利用这一特性。构效关系研究产生了几个关键类似物，包括在羰基一侧引入联芳基以提高活性的一组类似物。其中几种联芳基类似物具有亚微摩尔活性，最有效的类似物的半数有效浓度（EC） = 22 nM。更重要的是，和几种联芳基酰胺（，，，）能够穿过血脑屏障（BBB），口服给药后在小鼠脑中显示出良好的药物水平。这些联芳基酰胺可能是进一步优化先导化合物以鉴定治疗朊病毒疾病潜在候选药物的良好起点。
