Orally-absorbed, small molecule microtubule-stabilizers for tauopathy treatment

用于治疗 tau 蛋白病的口服吸收小分子微管稳定剂

• 批准号: 8670685
• 负责人: KURT R. BRUNDEN
• 金额: $ 47.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670685
• 关键词: Acute; Alzheimer' s Disease; Animal Model; Antifungal Agents; Axonal Transport; Binding; Bioavailable; Biological Assay; Brain; Cells; Clinical; Cognitive; Complex; Development; Dose; Evaluation; Female; Financial compensation; Frontotemporal Dementia; Heterocyclic Compounds; Hippocampus (Brain); Human; In Vitro; Intravenous; Investigation; Laboratories; Lead; Maximum Tolerated Dose; Mediating; Microtubule stabilizing agent; Microtubules; Mono-S; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Neuropil Threads; Nude Mice; Outcome; P-Glycoprotein; Pathology; Performance; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Property; Proteins; Pyridazines; Reporting; Research; Route; Safety; Series; Structure; Tauopathies; Testing; Therapeutic; Toxic effect; Transgenic Animals; Transgenic Mice; Water; Wild Type Mouse; base; chemical property; design; drug candidate; epothilone D; improved; in vivo; loss of function; member; mouse model; neuron loss; programs; protein aggregation; protein misfolding; public health relevance; screening; small molecule; tau Proteins; tau aggregation; tau function; treatment strategy

DESCRIPTION (provided by applicant): Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases which include Alzheimer's disease and frontotemporal dementias, the hyperphosphorylation and aggregation of the microtubule (MT)-associated protein tau is believed to have pathological consequences via toxic gain and/or loss of functions. Recent studies from our laboratories have demonstrated that treatment with low weekly doses of the brain-penetrant MT-stabilizing agent, epothilone D (epoD), resulted in improved axonal transport, reduced axonal dystrophy and decreased neuronal pathology in tau transgenic (Tg) mice. These results thus suggest that compensation for the loss of tau MT-stabilizing function may be a viable therapeutic strategy for the treatment of tauopathies. However, epoD and related congeners have potentially significant deficiencies as drug candidates. Furthermore, epoD is the only example of a brain-penetrant MT-stabilizing agent that has undergone in vivo efficacy studies in tau Tg animal models. As a result, the development and evaluation of additional CNS-active MT-stabilizing agents is clearly desirable so as to identify alternative and improved clinical candidates. The focus of the proposed research plan is to investigate a related series of triazolopyrimidine, phenylpyrimidine, pyridopyridazine, pyridotriazine, and pyridazine MT-stabilizing compounds. After synthesis, compounds will be evaluated for MT-stabilizing activities, ADME-PK properties, and potential safety liabilities (Aim 1). The most promising MT-stabilizers (d15) found to be brain-penetrant and orally bioavailable will progress to an assessment of pharmacodynamic effect and acute toxicity (Aim 2), followed by longer-term 1-month safety assessments (Aim 3) to identify preferred candidates (1-2) that will undergo efficacy studies in an established Tg mouse model of tauopathy (Aim 4).

描述（由申请人提供）：蛋白质错误折叠和聚集构成了许多神经退行性疾病的潜在共同病理机制。在tau蛋白病（包括阿尔茨海默氏病和额颞叶痴呆）的一组神经退行性疾病中，微管（MT）相关蛋白tau的过度磷酸化和聚集被认为通过毒性增加和/或功能丧失而产生病理后果。我们实验室最近的研究表明，每周低剂量的脑渗透性 MT 稳定剂埃博霉素 D (epoD) 治疗可改善 tau 转基因 (Tg) 小鼠的轴突运输、减少轴突营养不良和神经元病理。因此，这些结果表明，补偿 tau MT 稳定功能的丧失可能是治疗 tau 病的可行治疗策略。然而，epoD 和相关同源物作为候选药物存在潜在的重大缺陷。此外，epoD 是唯一一个在 tau Tg 动物模型中进行体内功效研究的脑渗透性 MT 稳定剂。因此，显然需要开发和评估其他 CNS 活性 MT 稳定剂，以便确定替代和改进的临床候选药物。该研究计划的重点是研究一系列相关的三唑并嘧啶、苯基嘧啶、吡啶并哒嗪、吡啶并三嗪和哒嗪MT稳定化合物。合成后，将评估化合物的 MT 稳定活性、ADME-PK 特性和潜在的安全性（目标 1）。最有前途的脑渗透性和口服生物利用度的 MT 稳定剂 (d15) 将进行药效效应和急性毒性评估（目标 2），随后进行为期 1 个月的长期安全性评估（目标 3），以确定首选候选药物 (1-2)，这些候选药物将在已建立的 Tg 小鼠模型中进行疗效研究（目标 4）。