Optimization of microtubule-stabilizing triazolopyrimidines as therapeutics for Alzheimer's disease and related tauopathies

优化微管稳定三唑并嘧啶作为阿尔茨海默病和相关 tau蛋白病的治疗方法

• 批准号: 10398425
• 负责人: KURT R. BRUNDEN
• 金额: $ 15.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398425
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Axon; Axonal Transport; Biological; Brain; Cellular Assay; Chemicals; Clinical; Data; Docking; Drug Kinetics; Equipment; Evaluation; Future; Goals; Lead; Microtubule Stabilization; Microtubule stabilizing agent; Microtubule-Associated Proteins; Microtubules; Modeling; Mus; Natural Products; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Patients; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacology and Toxicology; Phase Ib Clinical Trial; Phosphorylation; Process; Property; Safety; Scoring Method; Series; Structure; Tauopathies; Testing; Toxicology; Transgenic Mice; Transgenic Organisms; analog; cognitive performance; density; efficacy study; epothilone D; improved; in silico; lead candidate; neuron loss; pharmacokinetics and pharmacodynamics; preclinical safety; programs; tau Proteins; tau phosphorylation

PROJECT SUMMARY A group of neurodegenerative diseases referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by the presence within brain neurons of inclusions comprised of hyperphosphorylated forms of tau protein. Tau is normally a microtubule (MT)-associated protein that appears to provide stability to MTs in axons, and excessive phosphorylation of tau in tauopathies promotes its disengagement from MTs and misfolding into oligomeric and fibrillar structures. This results in increased MT dynamicity, reduced MT density and altered axonal transport in transgenic (Tg) mouse tauopathy models, with evidence of similar MT deficits in AD brain that likely contribute to neurodegeneration. We previously demonstrated that administration of the brain-penetrant MT-stabilizing natural product, epothilone D (EpoD), to Tg tauopathy mice resulted in dramatic improvements in several key endpoints, including increased MT density, reduced axonal dystrophy, diminished tau pathology and a lowering of neuron loss with improved cognitive performance. Although EpoD progressed to a small Phase 1b clinical trial in AD patients, its future clinical advancement is uncertain. Thus, there would be considerable value in identifying alternative MT-stabilizing agents that could undergo more thorough testing in AD and tauopathy patients. In this regard, we have synthesized and evaluated a series of non-natural product MT-stabilizing compounds (triazolopyrimidines or TPDs, and phenylpyrimidines), and an evaluation of these compounds has led to an understanding of key structure-activity correlates. An assessment of pharmacokinetic (PK) and pharmacodynamics (PD) profiles of select examples resulted in the identification of a lead TPD that has recently shown highly beneficial activity in a Tg mouse tauopathy model. We propose in this early-stage U01 program to utilize lessons learned in our initial medicinal chemistry exploration to conduct a highly focused chemical optimization program to identify a candidate TPD compound suitable for entry into IND-enabling pre-clinical safety pharmacology and toxicology studies. We will utilize in silico computational docking studies to select and prioritize patentable TPD congeners for activity testing in established cellular assays. Data from these studies will be utilized to refine the scoring method and re-evaluate the prioritization of in silico hits, leading to additional iterative cycles of synthesis and biological evaluations. The most active compounds identified through this process will be assessed for brain exposure in mice, and preferred examples will undergo complete PK and PD testing. Ultimately, a select few analogs with superior PK/PD properties will be assessed for safety/tolerability in mice, with the best candidate advancing to efficacy studies in an established Tg mouse tauopathy model. The overall project objective is to identify a patentable lead candidate TPD that would be eligible for entry in IND-enabling studies to be conducted after completion of this early-stage U01 program.

项目摘要 一组称为tau蛋白病的神经退行性疾病，包括阿尔茨海默病（AD）， 其特征在于在脑神经元内存在包含过度磷酸化形式的 tau蛋白。Tau通常是微管（MT）相关蛋白，其似乎在细胞内为MT提供稳定性。 轴突，并且tau蛋白病中tau蛋白的过度磷酸化促进其从MT脱离， 错误折叠成低聚物和纤维状结构。这导致MT动态性增加，MT 在转基因（Tg）小鼠tau蛋白病模型中， AD大脑中可能导致神经退行性变的缺陷。我们之前已经证明， 将脑渗透MT稳定天然产物埃坡霉素D（EpoD）施用至Tg tau病变 小鼠在几个关键终点上得到了显着的改善，包括MT密度增加， 轴突营养不良，减少tau病理和降低神经元损失，改善认知功能 性能虽然EpoD进展到AD患者的小型1b期临床试验，但其未来的临床试验 进步是不确定的。因此，确定其他MT稳定方法将具有相当大的价值 这些药物可以在AD和tau蛋白病患者中进行更彻底的测试。我们已就此 合成并评价了一系列非天然产物MT稳定化合物（三唑并嘧啶或 TPD和苯基嘧啶），并且对这些化合物的评价已经导致了对关键化合物的理解。 构效关系评估的药代动力学（PK）和药效学（PD）特征 选择的例子导致了一个领先的TPD的鉴定，最近显示出高度有益的活动， Tg小鼠tau蛋白病模型。我们建议在这个早期阶段的U 01计划中利用我们在 初步的药物化学探索，进行高度集中的化学优化计划，以确定 适合进入IND使能临床前安全药理学和毒理学的候选TPD化合物 问题研究我们将利用计算机计算对接研究来选择和优先考虑可专利的TPD 在已建立的细胞试验中进行活性测试的同系物。这些研究的数据将用于完善 评分方法，并重新评估计算机模拟命中的优先级，导致额外的迭代周期， 合成和生物学评价。通过这一过程确定的最活跃的化合物将是 评估小鼠中的脑暴露，并且优选的实施例将经历完整的PK和PD测试。 最终，将评估具有上级PK/PD特性的选定少数类似物在小鼠中的安全性/耐受性， 其中最佳候选物在已建立的Tg小鼠tau蛋白病模型中进行功效研究。整体 项目目标是确定一个可申请专利的领先候选TPD，该TPD将有资格进入IND， 研究将在完成这一早期U 01计划后进行。