Development of Small Molecule Orexin Receptor Agonists for Treating Narcolepsy

治疗发作性睡病的小分子食欲素受体激动剂的开发

• 批准号: 7937840
• 负责人: JEF KAREL DE BRABANDER
• 金额: $ 48.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937840
• 关键词: Address; Adverse effects; Affect; Agonist; American; Animal Model; Area; Back; Basic Science; Biological; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Breeding; Cataplexy; Chemicals; Development; Diagnosis; Diet; Disease; Drug Kinetics; Engineering; Epilepsy; Evaluation; Excretory function; Exhibits; G-Protein-Coupled Receptors; Goals; Human; Humulus; Hypothalamic structure; In Vitro; Individual; Laboratories; Leptin; Life; Mental Depression; Metabolic; Metabolism; Modeling; Mouse Strains; Muscle function; Narcolepsy; Neurons; Neuropeptides; Obesity; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plant Roots; Play; Property; Replacement Therapy; Research; Role; Seasons; Signal Transduction; Sleep; Sleep Paralysis; Sleep Wake Cycle; Staging; Structure-Activity Relationship; Symptoms; Syndrome; Synthesis Chemistry; Technical Expertise; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Animals; Transgenic Mice; Translating; Translational Research; Wakefulness; absorption; analog; animal efficacy; base; design; drug candidate; drug development; feeding; high throughput screening; human disease; hypocretin; improved; in vitro Assay; in vivo; multidisciplinary; neurochemistry; palliative; postnatal; pre-clinical; prevent; programs; receptor; scaffold; small molecule; therapy development

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.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化科学和特定挑战主题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/癫痫的临床前药物。发作性睡病是一种使人衰弱的疾病，其特征是无法适当地保持清醒、睡眠发作、肌肉功能突然丧失和睡眠瘫痪。发作性睡病是一种非进行性的终身疾病，估计影响1/1，000 ~ 1/2，000人（200，000美国人），并且经常被诊断不足或被误认为抑郁症，癫痫或药物副作用。目前可用于治疗发作性睡病的是姑息性的、以药物治疗为导向的药物治疗。因此，它们不仅对纠正潜在的神经化学缺陷无效，而且还表现出各种不期望的副作用。越来越多的证据表明，下丘脑神经肽，称为食欲素（也hypocretins），在睡眠/觉醒控制中起重要作用，发作性睡病是食欲素缺乏综合征。已经被工程化以紧密模拟人类发作性睡病中的神经化学情况（即具有食欲素神经元的出生后损失）的转基因小鼠品系表现出发作性睡病/紧张症的所有症状，并且可以通过提供外源性食欲素来治愈。然而，食欲素是肽，因此口服无活性且血脑屏障不可渗透，并且不能用作治疗剂。使用高通量筛选，我们已经确定了第一食欲素受体特异性小分子激动剂。我们提出了一个药物化学计划，以提高其效力和药代动力学特性，以提供大脑穿透的临床前候选人，用于在人类嗜睡症的转基因动物模型中进行概念验证研究。一个拥有生物、化学和药理学专业知识的独特的多学科团队已经组建起来，通过多管齐下的方法来解决这个问题。合成化学将用于小分子食欲素激动剂的迭代合成和优化，研究将以效价和选择性的全面体外评估以及药物样性质的药理学评估为指导。最后，将在人发作性睡病的体内动物模型中评价所选候选物。我们的团队非常适合实现上述总体目标。食欲素的发现，以及它们在睡眠/觉醒周期和嗜睡症中的作用，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。结合这些优势，在食欲素生物学与合成化学和药理学专业知识，有很大的可能性，这个团队将提供第一个小分子临床前候选人食欲素替代疗法。我们建议开发用于治疗嗜睡症的药物样临床前候选药物，嗜睡症是一种使人衰弱的疾病，估计影响约20万美国人。目前可用的治疗嗜睡症表现出各种不良的副作用，是无效的纠正潜在的神经化学缺陷。我们提出的研究是高度相关的，因为它试图将基础科学发现，即食欲素缺乏是嗜睡症的根源，转化为一种旨在取代内源性食欲素的候选药物，从而为人类嗜睡症提供潜在的治疗方法。