Discovery and Preliminary Structure鈥揂ctivity Relationship of Arylpiperazines as Novel, Brain-Penetrant Antiprion Compounds

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• 作者：Zhe Li ; Joel R. Gever ; Satish Rao ; Kartika Widjaja ; Stanley B. Prusiner ; B. Michael Silber
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：4
• 期：4
• 页码：397-401
• 全文大小：254K
• 年卷期：v.4,no.4(April 11, 2013)
• ISSN：1948-5875

文摘

Creutzfeldt-Jakob disease and kuru in humans, BSE in cattle, and scrapie in sheep are fatal neurodegenerative disorders. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrP^Sc) of a normally benign, host cellular protein, denoted PrP^C. We employed high-throughput screening enzyme-linked immunosorbent assays to evaluate compounds for their ability to reduce the level of PrP^Sc in Rocky Mountain Laboratory 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 <b>1b>, <b>7b>, <b>13b>, and <b>19b>, displayed moderate antiprion activity with ECb>50b> values in the micromolar range. Key analogues were designed and synthesized on the basis of the structure鈥揳ctivity relationship, with analogues <b>41b>, <b>44b>, <b>46b>, and <b>47b> found to have submicromolar potency. Analogues <b>41b> and <b>44b> were able to penetrate the blood鈥揵rain barrier 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.<br>

Keywords:

Neurodegenerative diseases; prion disease; Creutzfeldt-Jakob disease; piperazine; arylpiperazine; structure鈭抋ctivity relationship