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Optimization of small molecule SERCA2b activators to inhibit neuron loss in Alzheimer's disease

优化小分子 SERCA2b 激活剂抑制阿尔茨海默病神经元损失

基本信息

批准号：
10689427
负责人：
Russell Dahl
金额：
$ 52.91万
依托单位：
NEURODON LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689427
关键词：
3xTg-AD mouse AD transgenic mice Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Amyloid beta-Protein Precursor Animal Model Apoptosis Apoptotic Biological Markers Brain Ca(2+)-Transporting ATPase Calcium Cardiac Cell Death Induction Cell model Chemistry Clinical Clinical Research Clinical Trials Cognition Cognitive deficits Data Development Disease Disease Progression Drug Targeting Endoplasmic Reticulum Enzyme Inhibition Evaluation Formulation Functional disorder Future Gene Mutation Generations Genes Goals Health Homeostasis Human In Vitro Induction of Apoptosis Lead Learning Legal patent Link MAPT gene Measures Memory Memory Loss Modality Mus Nerve Degeneration Neurons Oral Oral Administration Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Physiological Preparation Probability Process Proteins Public Health Pump Research Risk Safety Small Business Innovation Research Grant Small Business Technology Transfer Research Symptoms Synapses Testing Therapeutic Toxicology Transgenic Mice Work biomarker driven brain cell clinical translation drug development drug discovery efficacy study endoplasmic reticulum stress improved in vivo innovation manufacture mouse model multidisciplinary neuroinflammation neuron loss neuropathology neuroprotection new chemical entity novel novel therapeutics patient population pharmacologic pre-clinical preclinical development preclinical study presenilin-1 prevent programs response scale up small molecule sobriety solid state specific biomarkers success tau Proteins theories therapeutic candidate transgenic model of alzheimer disease

项目摘要

In this Phase IIB SBIR project for Alzheimer’s disease (AD) drug development, Neurodon LLC proposes to conduct preclinical development and IND-enabling activities on our novel, orally available lead and backup compounds that, in our preceding Phase II project, showed neuroprotection and beneficial effects on learning and memory in a transgenic model of AD. Despite the enormity of AD as a national public health burden, the therapeutic options are very limited. The few approved drugs treat only symptoms, and there are no disease- modifying therapies available. All of the disease-modifying clinical trials have failed, with most drug targets being amyloid or amyloid-related. With this patient population set to almost triple over the next 30 years, there is an urgent need for disease-modifying therapies, specifically alternatives to amyloid-targeted drugs. Neuron loss is the only physiological phenomena that has been directly linked to the cognition and memory loss in patients, and a major cause of this brain cell loss in AD is endoplasmic reticulum (ER) stress-induced apoptosis caused by aberrant intracellular Ca2+ homeostasis. Neurodon’s patented, small molecule activators of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), correct neuronal calcium handling, rescue brain cells in vitro and in vivo, improve learning and memory in the APP/PS1 double transgenic mouse model of AD, and reduce ER stress and apoptosis markers in vivo, enabling biomarker- driven drug discovery and an improved probability of clinical success. Our Phase II research met the milestones of nominating orally active lead and backup compounds that show efficacy in an animal model of AD. Our goal of delivering an IND for AD will be accomplished by pursuing the following Aims: 1) Chemistry scale-up, pre-formulation, ADME, and PK on our lead SERCA2b activator and 2 backup compounds. 2) To assess the effects of SERCA2b activators on cognition and profiling AD mechanism-specific biomarkers in vivo. 3) Perform necessary preclinical studies on a selected SERCA2b activator new chemical entity (NCE) and backup compound in preparation for IND filing. The results of these Aims will be the generation of efficacy, safety, and CMC information to complete a submission-ready FDA IND application for a new, disease- modifying therapeutic for AD.

在阿尔茨海默病（AD）药物开发的IIB期SBIR项目中，Neurodon LLC建议对我们的新型口服先导药物和备用药物进行临床前开发和IND启动活动在我们之前的第二阶段项目中，这些化合物显示出神经保护作用和对学习的有益作用。和记忆的关系。尽管AD作为国家公共卫生负担的严重性，治疗选择非常有限。少数几种被批准的药物只能治疗症状，没有疾病- 修改可用的疗法。所有改善疾病的临床试验都失败了，大多数药物靶点是淀粉样蛋白或与淀粉样蛋白相关的。随着这一患者群体在未来30年内几乎增加两倍，目前迫切需要改善疾病的治疗方法，特别是淀粉样蛋白靶向药物的替代品。神经元丧失是唯一与认知和记忆丧失直接相关的生理现象， AD患者脑细胞丢失的主要原因是内质网（ER）应激诱导的细胞内钙稳态异常引起的细胞凋亡。Neurodon的专利，小分子活化剂主要的ER Ca 2+处理蛋白，肌质/内质网Ca 2 +-ATP酶（SERCA），正确的神经元钙处理，在体外和体内拯救脑细胞，改善学习记忆中的APP/PS1双 AD转基因小鼠模型，并减少ER应激和凋亡标志物在体内，使生物标志物- 驱动的药物发现和提高的临床成功概率。我们的第二阶段研究符合提名口服活性先导化合物和备用化合物的里程碑，这些化合物在以下动物模型中显示出功效： AD.我们将通过追求以下目标来实现为AD提供IND的目标：1）化学我们的主要SERCA 2b激活剂和2种备用化合物的放大、预配制、ADME和PK。2)到评估SERCA 2b激活剂对认知的影响，并分析AD机制特异性生物标志物， vivo. 3)对选定的SERCA 2b激活剂新化学实体（NCE）进行必要的临床前研究和备用化合物以备IND申请。这些目标的结果将是产生功效，安全性和CMC信息，以完成新疾病的FDA IND申请，用于AD的改良治疗剂。