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Early development of small molecule neuroprotectants.

小分子神经保护剂的早期开发。

基本信息

批准号：
10241448
负责人：
Thomas D Bannister
金额：
$ 73.31万
依托单位：
SCRIPPS FLORIDA
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：
2018-08-15 至 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241448
关键词：
ADP ribosylation Affinity Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Axotomy Behavioral Symptoms Binding Proteins Bioavailable Biological Biological Assay Biological Availability Biological Markers Brain Brain Ischemia Cell Death Cell Survival Cells Cellular Assay Chemicals Clinical Clinical Trials Consumption Cytochrome P450 Deposition Development Disease Drug Kinetics Evaluation Exhibits Exposure to Family Half-Life In Vitro Injections Injury Investigation Investigational Drugs KDR gene Knowledge Lead Link Liver Microsomes Metabolic Modeling Molecular Motor Multiple Sclerosis Mus Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurologic Neuronal Injury Neurons Neuroprotective Agents Oral Oxidative Stress Parkinson Disease Pathogenicity Pathway interactions Penetration Pharmaceutical Chemistry Pharmacology Phosphotransferases Plasma Plasma Proteins PrP Prevention Prion Diseases Property Proteins Proteomics Recovery Reperfusion Injury Rodent Model Safety Series Spices Structure-Activity Relationship Study Subject Testing Therapeutic Time Toxic effect Wallerian Degeneration analog base blood-brain barrier penetration cheminformatics design drug metabolism effective therapy excitotoxicity high throughput screening improved in vivo inhibitor/antagonist knock-down lead optimization lead series misfolded protein motor function improvement motor neuron function motor symptom mouse model muscle strength nanomolar neuron loss neuropathology neuroprotection neurotoxicity new therapeutic target novel overexpression preclinical efficacy preservation prevent protein misfolding receptor restoration scaffold screening small molecule urinary

项目摘要

SUMMARY NAD depletion occurs after excitotoxic insults and oxidative stress and causes neuronal death in several rodent models of neurodegenerative conditions, including models for brain ischemia/reperfusion injury and Wallerian degeneration. We have recently discovered that NAD depletion is also the primary cause of neuronal death induced by exposure to a misfolded and toxic form of the amyloidogenic prion protein (TPrP). NAD replenishment reversed the fate of TPrP-injured neurons in culture and improved motor function in a mouse model of prion disease. Therefore, our study established NAD restoration as a new therapeutic target for protein misfolding neurodegenerative diseases, a family of diseases that includes Alzheimer's, Parkinson's, prion diseases and amyotrophic lateral sclerosis (ALS). We developed a high- throughput screening strategy to identify NAD-dependent neuroprotective small molecules in the misfolded protein toxicity paradigm and then conducted a screening campaign. We identified and selected four chemical series providing complete neuroprotection and preserving NAD levels with nanomolar potency. One compound was tested in a murine model of ALS and improved the mice's muscle strength and motor function. We will conduct molecular mode of action studies for each chemical series, in conjunction with potency and drug metabolism and pharmacokinetic (DMPK) studies, to guide selection of the top lead. Lead optimization will be done through iterative rounds of structure-activity relationship studies and subjecting analogs to a series of in vitro and in vivo assays for potency, selectivity and absence of undesired off-target effects, as well as favorable DMPK properties including brain penetration. This workplan will deliver a novel small molecule neuroprotectant poised for investigational new drug (IND)–enabling studies and ultimately for the treatment of neurological conditions linked to a deficit in NAD.

总结 NAD耗竭发生在兴奋性毒性损伤和氧化应激后，并导致几个神经元死亡。神经变性病症的啮齿动物模型，包括脑缺血/再灌注损伤的模型，以及沃勒变性。我们最近发现，NAD的消耗也是导致肥胖的主要原因。暴露于错误折叠和毒性形式的淀粉样蛋白朊蛋白诱导的神经元死亡（TPrP）。补充NAD逆转了培养物中TPrP损伤神经元的命运，并改善了运动神经元的功能。在朊病毒病小鼠模型中发挥作用。因此，我们的研究建立了NAD恢复作为一种新的蛋白质错误折叠神经退行性疾病的治疗靶点，该疾病家族包括阿尔茨海默氏症、帕金森氏症、朊病毒疾病和肌萎缩侧索硬化症（ALS）。我们开发了一个高- 通量筛选策略，以鉴定错误折叠中NAD依赖性神经保护性小分子，蛋白质毒性范例，然后进行筛选活动。我们确定并挑选了四个化学系列提供完整的神经保护和保护NAD水平与纳摩尔效力。一种化合物在ALS小鼠模型中进行了测试，并改善了小鼠的肌肉力量和运动能力功能我们将对每个化学系列进行分子作用模式研究，效价和药物代谢及药代动力学（DMPK）研究，以指导首选药物的选择。铅优化将通过迭代轮的结构-活性关系研究和主题类似物的一系列体外和体内测定的效力，选择性和不存在不希望的脱靶效果，以及有利的DMPK性质，包括脑渗透。这份工作计划将提供一本小说小分子神经保护剂准备用于研究性新药（IND）研究，并最终用于治疗与NAD缺陷相关的神经系统疾病。