Development of Small Molecule Orexin Receptor Agonists for Treating Narcolepsy

描述（由申请人提供）：本申请涉及广泛的挑战领域 (15)：转化科学和具体挑战主题 15-NS-104：早期治疗开发。我们建议开发和评估小分子食欲素受体激动剂作为治疗发作性睡病/猝倒症的临床前先导药物。发作性睡病是一种使人衰弱的疾病，其特征是无法正确保持清醒、睡眠发作、肌肉功能突然丧失和睡眠麻痹。发作性睡病是一种非进行性的终生疾病，估计影响 1/1,000 ~ 1/2,000 人（200,000 名美国人），并且经常被诊断不足或误认为是抑郁症、癫痫或药物副作用。目前针对发作性睡病的可用治疗方法是姑息性、针对症状的药物疗法。因此，它们不仅无法有效纠正潜在的神经化学缺陷，而且还表现出各种不良副作用。越来越多的证据表明，下丘脑神经肽，称为食欲素（也称为下丘脑分泌素），在睡眠/觉醒控制中发挥着重要作用，并且发作性睡病是一种食欲素缺乏综合征。转基因小鼠品系经过工程改造，可以密切模仿人类嗜睡症患者的神经化学状况，即出生后食欲素神经元缺失，表现出嗜睡症/猝倒症的所有症状，并且可以通过提供外源性食欲素来治愈。然而，食欲素是肽，因此口服无活性且不能渗透血脑屏障，不能用作治疗剂。通过高通量筛选，我们鉴定出了第一个食欲素受体特异性小分子激动剂。我们提出了一项药物化学计划，以提高其效力和药代动力学特性，以提供可穿透大脑的临床前候选药物，用于人类发作性睡病转基因动物模型的概念验证研究。我们组建了一支具有生物、化学和药理学专业知识的独特多学科团队，通过多管齐下的方法来解决这一问题。合成化学将用于小分子食欲素激动剂的迭代合成和优化，这些研究将以效力和选择性的全面体外评估以及药物样特性的药理学评估为指导。最后，选定的候选者将在人类嗜睡症的体内动物模型中进行评估。我们的团队非常适合实现上述总体目标。食欲素的发现及其在睡眠/觉醒周期和发作性睡病中的作用源自柳泽博士的实验室，他还开发了完全重现人类疾病的转基因动物模型。将食欲素生物学的这些优势与合成化学和药理学专业知识相结合，该团队很有可能为食欲素替代疗法提供第一个小分子临床前候选药物。我们建议开发类似药物的临床前候选药物来治疗发作性睡病，这是一种使人衰弱的疾病，估计影响大约 200,000 名美国人。目前针对发作性睡病的可用治疗方法表现出各种不良副作用，并且对于纠正潜在的神经化学缺陷无效。我们提出的研究具有高度相关性，因为它试图将食欲素缺乏是发作性睡病根源的基础科学发现转化为旨在替代内源性食欲素的候选药物，从而为人类发作性睡病提供潜在的治疗方法。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science, and Specific Challenge Topic 15-NS-104: Early Stage Therapy Development. We propose to develop and evaluate small-molecule orexin receptor agonists as preclinical leads for the treatment of narcolepsy/cataplexy. Narcolepsy is a debilitating disorder characterized by an inability to properly maintain wakefulness, sleep attacks, a sudden loss of muscle function, and sleep paralysis. Narcolepsy is a non-progressive, life-long condition, which is estimated to affect 1/1,000 ~ 1/2,000 individuals (200,000 Americans) and is often under-diagnosed or mistaken for depression, epilepsy or medication side effects. Current available treatments for narcolepsy are palliative, symptom-oriented pharmacotherapies. Thus, not only are they ineffective for correcting the underlying neurochemical deficits, but they also exhibit various undesirable side-effects. Accumulating evidence indicates that the hypothalamic neuropeptides, termed orexins (also hypocretins), play an important role in sleep/wake control and that narcolepsy is an orexin-deficiency syndrome. Transgenic mouse strains that have been engineered to closely mimic the neurochemical situation in human narcoleptics, i.e. with a postnatal loss of orexin neurons, exhibit all symptoms of narcolepsy/cataplexy and can be cured by providing exogenous orexin. However, orexins are peptides, thus orally inactive and blood-brain barrier impermeable, and cannot be used as a therapeutic agent. Using high throughput screening, we have identified the first orexin receptor-specific small molecule agonists. We propose a medicinal chemistry program to improve their potency and pharmacokinetic properties to provide brain penetrable pre-clinical candidates for use in proof-of-concept studies in a transgenic animal model of human narcolepsy. A unique multidisciplinary team with biological, chemical, and pharmacological expertise has been assembled to tackle this problem via a multi-pronged approach. Synthetic chemistry will be deployed for the iterative synthesis and optimization of small molecule orexin agonists, studies which will be guided by a comprehensive in vitro evaluation of potency and selectivity, and pharmacological assessment for drug-like properties. Finally, selected candidates will be evaluated in in vivo animal models of human narcolepsy. Our team is ideally suited to achieve the above stated overall goal. The discovery of orexins, and their role in sleep/wake cycles and narcolepsy, emanated from the laboratory of Dr. Yanagisawa, who also developed the transgenic animal models that fully recapitulate the human disease. Combining these strengths in orexin biology with synthetic chemistry and pharmacological expertise, there is a high likelihood that this team will provide the first small molecule preclinical candidates for orexin replacement therapy. We propose the development of drug-like preclinical candidates for the treatment of narcolepsy, a debilitating disorder that is estimated to affect approximately 200,000 Americans. Current available treatments for narcolepsy exhibit various undesirable side-effects and are ineffective for correcting the underlying neurochemical deficits. Our proposed research is highly relevant, as it seeks to translate the basic science finding that orexin deficiency is at the root of narcolepsy, into a drug candidate that is designed to replace endogenous orexin, and as such provide a potential cure for human narcolepsy.