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

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。就tau病变而言，包括阿尔茨海默病和额颞叶痴呆在内的一组神经退行性疾病，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/或功能丧失具有病理后果。我们实验室最近的研究表明，在tau转基因（Tg）小鼠中，每周使用低剂量的脑渗透mt稳定剂epothilone D （epoD）治疗可改善轴突运输，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及其相关同源物作为候选药物存在潜在的重大缺陷。此外，epoD是唯一在tau Tg动物模型中进行体内疗效研究的脑渗透mt稳定剂。因此，开发和评估额外的cns活性mt稳定剂显然是可取的，以便确定替代和改进的临床候选药物。本研究计划的重点是研究相关系列的三唑嘧啶、苯基嘧啶、吡啶吡嗪、吡啶多三嗪和吡啶嘧啶mt稳定化合物。合成后，将评估化合物的mt稳定活性、ADME-PK性质和潜在的安全性（Aim 1）。最有希望的mt -稳定剂（d15）被发现具有脑渗透性和口服生物可利用性，将进行药效学效果和急性毒性评估（Aim 2），随后进行为期1个月的长期安全性评估（Aim 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小鼠牛头病模型中进行疗效研究（Aim 4）。

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).