Early development of small molecule neuroprotectants.

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。 在朊病毒疾病小鼠模型中的功能。因此，我们的研究确立了NAD修复是一种新的方法， 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。

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.