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: 8478876
• 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/8478876
• 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包括许多神经退行性疾病的潜在共同病理机制。在tau蛋白病（一组神经变性疾病，包括阿尔茨海默病和额颞痴呆）的情况下，微管（MT）相关蛋白tau的过度磷酸化和聚集被认为通过毒性获得和/或功能丧失而具有病理学后果。我们实验室最近的研究表明，每周低剂量的脑渗透MT-稳定剂埃坡霉素D（epoD）的治疗，导致改善轴突运输，减少轴突营养不良和减少tau转基因（Tg）小鼠的神经元病理。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蛋白病的可行治疗策略。然而，epoD和相关同系物作为候选药物具有潜在的重大缺陷。此外，epoD是在tau Tg动物模型中进行体内功效研究的脑渗透MT稳定剂的唯一实例。因此，开发和评价另外的CNS活性MT稳定剂显然是期望的，以便鉴定替代的和改进的临床候选物。拟议的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，将评价化合物的MT稳定活性、ADME-PK特性和潜在安全性责任（目的1）。被发现具有脑渗透性和口服生物可利用性的最有希望的MT稳定剂（d15）将进展到药效学作用和急性毒性的评估（目标2），随后是长期1个月安全性评估（目标3），以鉴定将在已建立的tau蛋白病Tg小鼠模型中进行功效研究的优选候选物（1-2）（目标4）。