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

描述(由申请人提供)：Reset Treateutics建议开发用于治疗发作性睡病的食欲素受体激动剂。发作性睡病是一种令人衰弱的终生疾病，其特征是白天过度嗜睡(EDS)、猝倒(双侧肌肉张力突然丧失)、催眠幻觉和睡眠瘫痪。在美国，发作性睡病影响了大约15万人，并对患者的生活质量产生了负面影响。人们普遍认为嗜睡症的主要原因是食欲素缺乏。食欲素是一对神经肽，由下丘脑外侧区的特定神经元群体表达。食欲素在大脑中起到了睡眠/清醒调节的稳定剂的作用，大多数患有发作性睡病和猝倒的患者脑脊液中的食欲素水平很低或检测不到。与发作性睡病相关的ED历史上一直使用包括苯丙胺和非苯丙胺配方在内的兴奋剂药物进行治疗。虽然这些药物是有效的，由于潜在的成瘾和副作用，较新的非刺激性唤醒药物是首选的(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病患者的猝倒。羟丁酸钠带有黑匣子警告，其分布受到限制。 到中心药房，因为它有可能被滥用。正因为如此，RESET预计，由于公认的人类发作性睡病的病因，食欲素受体激动剂可能成为治疗发作性睡病的黄金标准。Reset的药物发现计划将利用已经从高通量筛选中获得的四个高优先级化学系列，以识别对食欲素受体具有活性的化合物。这些系列的优先顺序将通过使用由美国国立卫生研究院提供的体外ADMET板来完成。新的分子将使用NIH选定的化学CRO来合成。这些分子将被设计成具有更好的效力、选择性、稳定性和血脑屏障穿透性。Reset的两个活体模型都包含重大创新。第一个模型采用麻醉范例中的活体浮现，以便有效地测量先导化合物对意识产生积极影响的能力。发作性睡病的活体小鼠模型的概念验证利用了专有的睡眠脑电软件，这对于可靠地分析啮齿动物的睡眠阶段是必不可少的。通过这一关键途径的化合物将与NIH承包商合作，进入启用IND的研究和第一阶段临床试验。

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.