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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.

概括 NAD 耗竭发生在兴奋性毒性损伤和氧化应激后，并导致多种神经元死亡神经退行性疾病的啮齿动物模型，包括脑缺血/再灌注损伤模型和华勒变性。我们最近发现，NAD 耗竭也是导致暴露于错误折叠且有毒的淀粉样朊病毒蛋白诱导的神经元死亡（TPrP）。 NAD 补充逆转了培养物中 TPrP 损伤神经元的命运并改善了运动能力在朊病毒病小鼠模型中发挥作用。因此，我们的研究确立了 NAD 修复作为一种新的方法。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病、帕金森病、朊病毒病和肌萎缩侧索硬化症 (ALS)。我们开发了一种高通量筛选策略，以识别错误折叠中 NAD 依赖性神经保护小分子蛋白质毒性范例，然后进行筛选活动。我们确定并选择了四个化学系列提供完整的神经保护并保持纳摩尔效力的 NAD 水平。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，并与药效以及药物代谢和药代动力学 (DMPK) 研究，以指导顶级先导药物的选择。带领优化将通过迭代的结构-活性关系研究和主题来完成类似于一系列体外和体内测定的效力、选择性和不存在不良脱靶的情况效果，以及有利的 DMPK 特性，包括脑渗透。该工作计划将带来新颖的小分子神经保护剂有望用于研究性新药（IND）研究并最终用于治疗与 NAD 缺乏相关的神经系统疾病。