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首页> 外文学位 >Arylsulfanyl Pyrazolones Block Mutant SOD1 Aggregation and have Potential Application for the Treatment of Amyotrophic Lateral Sclerosis.
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Arylsulfanyl Pyrazolones Block Mutant SOD1 Aggregation and have Potential Application for the Treatment of Amyotrophic Lateral Sclerosis.

机译：芳硫基吡唑啉酮可阻止突变型SOD1聚集，并可能在肌萎缩性侧索硬化症的治疗中应用。

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摘要

Amyotrophic Lateral Sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Active compounds that can be starting points for pursuing potential therapeutics were identified in a cell-based high throughput screening assay targeting ALS. One of the scaffolds assembled from the active hits was the arylsulfanyl pyrazolone (ASP) scaffold. Both potency and bioavailability of the ASP scaffold have been extensively improved via chemical modification. Original ASP hit compounds were determined to have poor metabolic/plasma stability, so the direct metabolite was identified. We subsequently synthesized ASP analogs that resolved this rapid metabolism problem. One of the ASP analogues with superior potency and predicted pharmacological properties was tested in vivo for pharmacokinetics and brain penetration and subsequently in an animal model of ALS. The analog showed sustained blood and brain levels in vivo and statistically significant activity in the mouse model of ALS, thus validating the scaffold as a therapeutic lead.
机译：肌萎缩性侧索硬化症（ALS）是目前无法治愈的一种孤儿神经退行性疾病。在针对ALS的基于细胞的高通量筛选分析中，鉴定了可以作为追求潜在疗法起点的活性化合物。由活性命中组装的支架之一是芳基硫烷基吡唑酮（ASP）支架。通过化学修饰，ASP支架的效能和生物利用度均得到了广泛提高。确定原始的ASP命中化合物代谢/血浆稳定性差，因此鉴定出直接代谢物。随后，我们合成了ASP类似物，从而解决了该快速代谢问题。在体内针对药代动力学和脑渗透测试了一种具有出色效价和预期药理特性的ASP类似物，随后在ALS动物模型中对其进行了测试。该类似物在ALS小鼠模型中显示出持续的体内血液和大脑水平，并在统计学上具有显着活性，因此证实该支架可作为治疗前导。

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  • 作者

    Chen, Tian.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 181 p.
  • 总页数 181
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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