Development of ferroptosis inhibitors for Huntington Disease

亨廷顿病铁死亡抑制剂的开发

• 批准号: 10461960
• 负责人: Brent R Stockwell
• 金额: $ 38.81万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461960
• 关键词: Adult; Aftercare; Animal Model; Apoptosis; Autopsy; Biological; Biological Availability; Brain; CAG repeat; Cell Death; Cells; Computer software; Corpus striatum structure; Cytochrome P450; Degenerative Disorder; Development; Disease; Disease model; Dose; Drug Kinetics; Effectiveness; Endoplasmic Reticulum; Enzymes; Esters; Flowcharts; Foundations; Gastrointestinal tract structure; Genes; Genetic Diseases; Glutamates; Human; Huntington Disease; Huntington gene; Immune; In Vitro; Inflammation Mediators; Inflammatory; Investigation; Lipid Peroxidation; Liver Microsomes; Measures; Metabolic; Modeling; Monitor; Mus; N-terminal; Nerve Degeneration; Neurologic; Oral; Pathway interactions; Patients; Pharmacodynamics; Phase; Plasma; Polyunsaturated Fatty Acids; Production; Property; Reporting; Role; Safety; Sampling; Series; Slice; Solubility; Structure-Activity Relationship; Testing; Therapeutic Agents; Toxic effect; analog; blood-brain barrier penetration; fatty acid metabolism; improved; in vivo; inhibitor; lipophilicity; mass spectrometric imaging; mouse model; neuroinflammation; neuron loss; neurotoxicity; novel therapeutic intervention; prevent

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.

项目摘要 费罗罗他汀是一种有效的铁铁蛋白抑制剂。这是一种潜在参与细胞死亡的非凋亡形式 许多退化性疾病。我们已经显示了FER-1在大脑切片模型中的有效性 亨廷顿氏病（HD）和谷氨酸毒性。然而，费罗罗他汀的药代动力学/药效学 （pk/pd）特性使其不适合在动物模型中进一步测试铁铁作用 疾病。我们已经制作了一系列的费罗抑素类似物来探索费罗汀的结构活性关系 （SAR）并改善活性以及代谢和血浆稳定性。尽管我们在 创建具有良好效力和血浆稳定性的代谢稳定的类似物，其他改进是 设想这可能会导致可以在体内剂量的高效，稳定的化合物。结果 研究将是一组优化化合物，用于研究脂质过氧化在A中的作用 亨廷顿疾病的小鼠模型。从长远来看，我们将能够使用这些优化化合物 探测脂质过氧化和铁铁作用在多种退化性疾病中的作用。