Optimization and evaluation of novel benzimidazoles for the treatment of Alzheimer's Disease

新型苯并咪唑类药物治疗阿尔茨海默病的优化与评价

• 批准号: 10654786
• 负责人: Kevin Hodgetts
• 金额: $ 121.31万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654786
• 关键词: Acetylation; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Anthelmintics; Autophagocytosis; Binding; Biological Assay; Brain; Carbamates; Central Nervous System Diseases; Cerebrospinal Fluid; Chemicals; Chemistry; Cognitive deficits; Cytoskeleton; Disease; Dose; Drug Combinations; Drug Kinetics; Drug Modulation; Evaluation; Exhibits; Goals; Half-Life; Hippocampus; Hospitals; Human; Impaired cognition; In Vitro; Ketones; Laboratories; Lead; Learning; Measures; Memory; Metabolic; Microtubule Stabilization; Microtubules; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Plasma; Polymers; Property; Reporting; Research; Safety; Services; Solubility; Structure; Synapses; Testing; Therapeutic; Time; Tubulin; Woman; Work; abnormally phosphorylated tau; analog; benzimidazole; benzimidazole analog; clinical development; design; drug development; drug discovery; efficacy evaluation; efficacy study; experience; improved; in vitro Assay; in vivo; in vivo evaluation; medical schools; mouse model; neurotoxic; novel; polymerization; pre-clinical; prevent; response; restoration; success; tau Proteins; tau aggregation; tau-1; translational potential

Project Summary/Abstract (30 lines) Tau protein stabilizes microtubules in neurons, but abnormal hyperphosphorylation of tau leads to aggregate formation. In addition, soluble tau intermediates are more neurotoxic than higher order aggregates, and are responsible for the cognitive dysfunction in AD. A beneficial AD treatment may be to enhance tau clearance. Mebendazole is an approved anthelmintic drug that binds to free tubulin. In a 14-day proof of concept study, we discovered that twice daily dosing of mebendazole (25 mg/kg, b.i.d.) significantly lowered tau protein levels in the cortex of 12 week old rTG4510 mice. Although mebendazole is used safely in humans, its poor solubility, metabolic stability, and pharmacokinetics, in particular for a CNS disease, limits its potential for translation to treat AD in human. Therefore, an exciting opportunity exists for medicinal chemistry optimization of both the PK and PD properties of novel benzimidazole analogs, which we believe will result in the discovery of a significantly improved molecule with the potential to treat AD. The specific aims to this proposal are: Aim 1. Medicinal chemistry optimization of tubulin binding, tau modulation and brain penetration of novel benzimidazoles. New analogs of mebendazole will be designed, synthesized, and characterized in the in vitro assays described in detail in the proposal. Chemistry approaches focus on increasing the solubility of new molecules and improving the stability of the vulnerable carbamate and ketone groups. Goals are to identify patentable novel chemical matter with improved in vitro drug-like properties and to determine the best compounds to advance to the Aim 2 pharmacokinetic and target engagement studies. Aim 2. Pharmacokinetics and target engagement studies of lead compounds in mice. The PK properties of compounds that satisfy the criteria 1-9 in Table 3 will be studied in mice, and those compounds with appropriate plasma and brain exposure will advance into in vivo studies to measure target engagement. The goal of the target engagement studies is to determine the effect of 28-day dosing of lead compounds on levels of total tau and p-tau in: (i) cerebrospinal fluid (CSF); and (ii) brain in the rTG4510 mouse model of AD. Aim 3. In vivo efficacy studies of the lead compounds in the rTG4510 mouse model. We will evaluate the efficacy of the lead compound in a longer, dose-response efficacy study in the rTG4510 mouse model of AD. Dosing will be determined from the PK and target engagement studies (Aim 2). We will study both: (i) preventative (early) treatment that will begin at 2 months, which is the time point of onset pathology, and continue for 3 months; and (ii) therapeutic (late) treatment that will start at 5 months, which is the start of cognitive decline ending at 8 months, when very severe pathology with cognitive deficits are exhibited. The goal is to identify a lead compound that gives: (i) a significant reduction in tau and p-tau levels in cortex and hippocampus; (ii) improvements in synaptic and neuronal markers; and (iii) restoration of memory and learning. 1

项目概要/摘要（30行） Tau蛋白稳定神经元中的微管，但Tau蛋白的异常过度磷酸化导致聚集 阵此外，可溶性tau中间体比高阶聚集体更具有神经毒性，并且是神经毒性的。 导致AD患者认知功能障碍。有益的AD治疗可以是增强tau清除。 甲苯咪唑是一种批准的驱虫药，结合自由微管蛋白。在为期14天的概念验证研究中，我们 发现每天两次给药甲苯咪唑（25 mg/kg，b.i.d.）显著降低tau蛋白水平， 12周龄rTG 4510小鼠的皮质。 尽管甲苯咪唑在人体中使用安全，但其溶解度、代谢稳定性和药代动力学较差， 特别是对于CNS疾病，限制了其翻译以治疗人类AD潜力。因此，一个令人兴奋的 存在优化新型苯并咪唑PK和PD性质的药物化学机会 类似物，我们相信这将导致发现一种显着改进的分子， 治疗AD。这项建议的具体目标是： 目标1。微管蛋白结合、tau蛋白调节和脑渗透的药物化学优化 苯并咪唑。甲苯咪唑的新类似物将在体外设计，合成和表征。 在提案中详细描述的测定。化学方法的重点是增加新化合物的溶解度， 分子，并提高脆弱的氨基甲酸酯和酮基团的稳定性。目标是确定 具有改进的体外药物样性质的可专利的新化学物质，并确定最佳的 化合物推进到目标2药代动力学和目标接合研究。 目标二。先导化合物在小鼠体内的药代动力学和靶向作用研究。的PK特性 将在小鼠中研究满足表3中的标准1-9的化合物，并且那些具有 适当的血浆和脑暴露将进入体内研究以测量靶结合。的 目标接合研究的目的是确定铅化合物28天给药对 在AD的rTG 4510小鼠模型中，（i）脑脊液（CSF）;和（ii）脑中的总tau和p-tau。 目标3。先导化合物在rTG 4510小鼠模型中的体内功效研究。我们将评估 在AD的rTG 4510小鼠模型中的较长的剂量-反应功效研究中的先导化合物的功效。 将根据PK和靶点结合研究确定给药（目的2）。我们将研究：（一） 预防性（早期）治疗，将在2个月（发病病理学时间点）开始开始，并持续 3个月;和（ii）治疗性（晚期）治疗，将在5个月时开始，这是认知下降的开始 在8个月时结束，此时表现出具有认知缺陷的非常严重的病理学。目标是确定一个 先导化合物，其提供：（i）皮质和海马中tau和p-tau水平的显著降低;（ii） 突触和神经元标记物的改善;和（iii）记忆和学习的恢复。 1