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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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

项目摘要/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会导致聚集形成。此外，可溶性 tau 中间体比高阶聚集体更具神经毒性，并且 AD 中认知功能障碍的原因。一种有益的 AD 治疗方法可能是增强 tau 蛋白清除率。甲苯达唑是一种经批准的驱虫药，可与游离微管蛋白结合。在为期 14 天的概念验证研究中，我们发现每天两次服用甲苯咪唑（25 mg/kg，b.i.d.）可显着降低 12 周龄 rTG4510 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，特别是对于中枢神经系统疾病，限制了其转化为治疗人类 AD 的潜力。因此，一场激动人心的新型苯并咪唑的 PK 和 PD 特性存在药物化学优化的机会类似物，我们相信这将导致发现一种显着改进的分子，有可能治疗AD。该提案的具体目标是：目标 1. 新型药物的微管蛋白结合、tau 调节和脑渗透的药物化学优化苯并咪唑类。新的甲苯咪唑类似物将在体外设计、合成和表征提案中详细描述了化验。化学方法侧重于增加新物质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类药特性的可专利新型化学物质，并确定最佳化合物推进 Aim 2 药代动力学和靶点参与研究。目标 2. 先导化合物在小鼠体内的药代动力学和靶点参与研究。 PK属性满足表 3 中标准 1-9 的化合物将在小鼠中进行研究，并且那些具有适当的血浆和大脑暴露将进入体内研究以测量目标参与度。这目标参与研究的目标是确定先导化合物 28 天给药对水平的影响总 tau 和 p-tau 的含量： (i) 脑脊液 (CSF)； (ii) rTG4510 AD 小鼠模型中的大脑。目标 3. 先导化合物在 rTG4510 小鼠模型中的体内功效研究。我们将评估在 rTG4510 AD 小鼠模型中进行的一项更长的剂量反应功效研究中，研究了先导化合物的功效。剂量将根据 PK 和目标参与研究（目标 2）确定。我们将研究两者：（i）预防性（早期）治疗将从 2 个月（即发病病理学的时间点）开始，并持续 3个月； (ii) 治疗性（晚期）治疗将在 5 个月时开始，此时认知能力开始下降 8个月时结束，此时表现出非常严重的病理学和认知缺陷。目标是确定一个先导化合物能够：（i）显着降低皮质和海马中的 tau 和 p-tau 水平； (二) 突触和神经元标记的改善； (iii) 记忆和学习的恢复。 1