Development of ferroptosis inhibitors for Huntington Disease

项目摘要 铁抑素是一种有效的铁下垂抑制剂，它是一种非凋亡性的细胞死亡形式，可能与 一些退化性疾病。我们已经在脑片模型中展示了Fer-1的有效性。 亨廷顿病(HD)和谷氨酸中毒。然而，铁抑素的药代动力学/药效学 (PK/PD)的特性使其不适合用于动物模型，以进一步测试铁性下垂在这些疾病中的作用 疾病。我们已经制作了一系列铁抑素类似物来探索铁抑素的构效关系 (Sar)，并改善活性、代谢和血浆稳定性。虽然我们在以下方面取得了重大进展 创造代谢稳定的类似物，具有良好的效力和血浆稳定性，其他改进包括 据设想，这可能会产生高度有效、稳定的化合物，可以在体内服用。其结果是 研究将是一套用于体内使用的优化化合物，以研究脂质过氧化在 亨廷顿病小鼠模型。从长远来看，我们将能够使用这些优化的化合物来 探讨脂质过氧化和铁下垂在多种退行性疾病中的作用。

Project Summary Ferrostatin is a potent inhibitor of ferroptosis; which is a non-apoptotic form of cell death potentially involved in a number of degenerative diseases. We have shown the effectiveness of Fer-1 in brain slice models of Huntington's disease (HD) and glutamate toxicity. However, ferrostatin's pharmacokinetic/pharmacodynamic (PK/PD) properties make it unsuitable for use in animal models to further test the role of ferroptosis in these diseases. We have made a series of ferrostatin analogs to explore ferrostatin's structure-activity relationship (SAR) and to improve activity and metabolic and plasma stability. While we have made significant progress in creating metabolically stable analogs with good potency and plasma stability, additional improvements are envisioned that could result in highly potent, stable compounds that could be dosed in vivo. The result of this investigation will be a set of optimized compounds for in vivo use to study the role of lipid peroxidation in a mouse model of Huntington Disease. In the longer term, we will be able to use these optimized compounds to probe the role of lipid peroxidation and ferroptosis in a variety of degenerative diseases.