Orexin Receptor Agonists for the Treatment of Excessive Daytime Sleepiness and Ca

描述（由申请人提供）：Reset Therapeutics拟开发用于治疗发作性睡病的食欲素受体激动剂。发作性睡病是一种使人衰弱的终身疾病，其特征是白天过度嗜睡（EDS）、cataepsy（突然双侧肌张力丧失）、临睡前幻觉和睡眠麻痹。在美国，嗜睡症影响着大约15万人，并对其患者的生活质量产生负面影响。 众所周知，发作性睡病的主要原因是食欲素缺乏。食欲素是由下丘脑外侧区的特定神经元群体表达的一对神经肽。食欲素作为大脑中睡眠/觉醒调节的稳定剂，并且大多数患有发作性睡病伴紧张症的患者在其脑脊液中具有低水平或不可检测水平的食欲素。 与发作性睡病相关的EDS历来用兴奋剂药物治疗，包括安非他明和非安非他明制剂。虽然这些药物是有效的，但由于潜在的成瘾和负面副作用，较新的非刺激性觉醒药物是首选（例如莫达非尼）。目前，只有一种药物，羟丁酸钠，被FDA批准用于治疗发作性睡眠患者的卡他汀。羟丁酸钠带有黑框警告，其分销受到限制 因为它有可能被滥用正因为如此，Reset预计食欲素受体激动剂可能成为治疗嗜睡症的金标准，因为这种疾病在人类中是公认的原因。 重置的药物发现计划将利用四个高优先级的化学系列，这些化学系列已经从高通量筛选中获得，以确定对食欲素受体有活性的化合物。这些系列的优先顺序将通过使用体外ADMET面板完成，通过NIH提供。新的分子将使用NIH选定的化学CRO合成。这些分子将被设计成具有改进的效力、选择性、稳定性和血脑屏障渗透性。Reset的两种体内模型都包含重大创新。第一个模型采用体内从麻醉中苏醒的范例，以有效地测量先导化合物积极影响意识的能力。发作性睡病的体内小鼠模型的概念验证使用专有的睡眠EEG软件，该软件对于可靠地分析啮齿动物的睡眠阶段至关重要。通过这一关键途径的化合物将与NIH承包商合作进入IND使能研究和I期临床试验。 公共卫生相关性：嗜睡症是一种使人衰弱的终身睡眠障碍，在美国影响大约15万人，并对其患者的生活质量产生负面影响。目前的药物只能治疗症状，主要是安非他明或其他兴奋剂，通常只有适度的效果，并可能有严重的副作用;阻碍他们的使用。众所周知，发作性睡病的主要原因是食欲素缺乏，因此Reset预期食欲素受体激动剂可以为发作性睡病患者提供生活质量的重大改善，并成为发作性睡病治疗的金标准。1

DESCRIPTION (provided by applicant): Reset Therapeutics proposes to develop orexin receptor agonists for the treatment of narcolepsy. Narcolepsy is a debilitating lifelong disorder characterized by excessive daytime sleepiness (EDS), cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucination and sleep paralysis. Narcolepsy affects approximately 150,000 people in the US and has a negative effect on the quality of life of its sufferers. It is well accepted that the primary cause of narcolepsy is due to orexin deficiency. The orexins are a pair of neuropeptides expressed by specific populations of neurons in the lateral hypothalamic area. The orexins act as a stabilizer of sleep/wake regulation in the brain and most patients that suffer from narcolepsy with cataplexy have low or undetectable levels of orexin in their cerebrospinal fluid. EDS associated with narcolepsy has historically been treated with stimulant medications including amphetamine and nonamphetamine formulations. Although these medications are effective, due to potential for addiction and negative side effects, newer nonstimulant wakefulness medications are preferred (e.g. modafinil). Currently, only one medication, sodium oxybate, is approved by the FDA for the treatment of cataplexy in narcoleptic patients. Sodium oxybate carries a black box warning and its distribution is restricted to the central pharmacy, due to its potential for abuse. Because of this, Reset anticipates that orexin receptor agonists could become the gold standard in narcolepsy treatment, due to the accepted cause of the disorder in humans. Reset's drug discovery program will utilize the four high priority chemical series that have already been obtained from a high throughput screen conducted to identify compounds active against the orexin receptors. Prioritization of these series will be completed through the use of an in vitro ADMET panel, made available through the NIH. New molecules will be synthesized using the NIH's selected chemistry CRO. The molecules will be designed to have improved potency, selectivity, stability and blood-brain barrier penetration. Reset's two in vivo models both contain significant innovations. The first model employs an in vivo emergence from anesthesia paradigm in order to efficiently measure the ability of lead compounds to positively affect consciousness. The proof of concept in vivo mouse model of narcolepsy utilizes proprietary sleep EEG software that is essential for reliably analyzing sleep stages in rodents. Compounds that pass through this critical path will progress into IND-enabling studies and Phase I clinical trials in collaboration with NIH contractors. PUBLIC HEALTH RELEVANCE: Narcolepsy is a debilitating lifelong sleep disorder that affects approximately 150,000 people in the US and has a negative effect on the quality of life of its sufferers. Current medications treat only the symptoms, mostly with amphetamines or other stimulants, are often only moderately effective and can have serious side effects; hampering their use. It is well accepted that the primary cause of narcolepsy is due to an orexin deficiency and thus Reset anticipates that orexin receptor agonists could provide a major improvement in the quality of life for narcoleptic patients and become the gold-standard in narcolepsy treatment. 1