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: 10745558
• 负责人: Kevin Hodgetts
• 金额: $ 80.47万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10745558
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Anthelmintics; Binding; Brain; Carbamates; Central Nervous System Diseases; Cerebrospinal Fluid; Chemicals; Chemistry; Cognitive deficits; Dose; Drug Kinetics; Evaluation; Exhibits; Goals; Hippocampus; Human; Impaired cognition; In Vitro; Ketones; Lead; Learning; Measures; Memory; Metabolic; Microtubule Stabilization; Mus; Nerve Degeneration; Neurons; Pathology; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Property; Solubility; Structure; Synapses; Testing; Therapeutic; Time; Tubulin; abnormally phosphorylated tau; analog; benzimidazole; benzimidazole analog; clinical development; design; efficacy evaluation; efficacy study; improved; in vitro Assay; in vivo; mouse model; neurotoxic; novel; parent project; response; restoration; tau Proteins; tau-1; translational potential

Project Summary/Abstract (Parent Project) 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

项目摘要/摘要（父母项目） tau蛋白稳定神经元中的微管，但tau异常的高磷酸化导致聚集 形成。另外，可溶性tau中间体比高阶聚集体更神经毒性，并且是 负责AD的认知功能障碍。有益的AD处理可能是提高TAU清除率。 Mebendazole是一种批准的驱虫药，与自由小管蛋白结合。在14天的概念证明中，我们 发现每天两次给甲苯二唑（25 mg/kg，b.i.d.）大大降低了tau蛋白水平 12周大的RTG4510小鼠的皮质。 尽管Mebendazole安全地用于人类，但其溶解度差，代谢稳定性和药代动力学，但 特别是对于中枢神经系统疾病，它限制了其翻译的潜力来治疗人类的AD。因此，令人兴奋 存在新型苯咪唑的PK和PD特性的药物化学优化的机会 类似物，我们认为这将导致发现一个显着改善的分子，并有可能 治疗广告。该提案的具体目的是： 目标1。小管蛋白结合，tau调节和脑渗透的药物化学优化 苯甲酰唑。在体外，将设计，合成和表征新的甲苯二唑的新类似物 提案中详细描述了分析。化学方法的重点是提高新的溶解度 分子并改善脆弱氨基甲酸酯和酮基的稳定性。目标是确定 可专利的新型化学物质具有改善的体外药物样特性，并确定最佳 化合物可以促进目标2药代动力学和目标参与研究。 目标2。小鼠铅化合物的药代动力学和靶向参与研究。 PK属性 在小鼠中将研究满足表3中标准1-9标准的化合物的 适当的血浆和大脑暴露将进展到体内研究中，以测量目标参与。这 目标参与研究的目标是确定铅化合物对水平的28天给药的影响 在：（i）脑脊液（CSF）中; （ii）AD的RTG4510小鼠模型中的大脑。 AIM 3。对RTG4510小鼠模型中铅化合物的体内功效研究。我们将评估 在RTG4510 AD的RTG4510小鼠模型中，铅化合物在更长的剂量反应效果研究中的功效。 剂量将从PK和目标参与研究（AIM 2）确定。我们将同时研究：（i） 预防性（早期）将从2个月开始，这是发作病理学的时间点，并继续 三个月； （ii）将从5个月开始的治疗（晚期）治疗，这是认知能力下降的开始 在8个月结束时，表现出非常严重的认知缺陷病理。目标是确定 铅化合物提供：（i）皮质和海马中的tau和p-tau水平显着降低； （ii） 突触和神经元标记的改善； （iii）恢复记忆和学习。 1