Developing Novel Dual CRF-R1/Orexin-1 Receptor Antagonists for Tobacco Dependence

开发新型双 CRF-R1/Orexin-1 受体拮抗剂来治疗烟草依赖

• 批准号: 8211781
• 负责人: Belew Mekonnen
• 金额: $ 30万
• 依托单位: HAGER BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211781
• 关键词: Acetylcholine; Address; Adult; Adverse effects; Agreement; Alcohol or Other Drugs use; Animal Model; Anxiety; Area; Behavioral; Biological; Biological Assay; Biological Testing; Biotechnology; Brain; Bupropion; CRF receptor type 1; Cardiovascular Diseases; Cells; Cessation of life; Chemicals; Collaborations; Complex; Consumption; Corticotropin-Releasing Hormone; Data; Disease; Dopamine; Drug Formulations; Drug Kinetics; Economic Burden; Equilibrium; Freedom; Goals; Grant; Headache; Health; Health Care Costs; Health Expenditures; Human; In Vitro; Inhibitory Concentration 50; Intellectual Property; Label; Lead; Letters; Ligands; Link; Literature; Malignant Neoplasms; Malignant neoplasm of lung; Mental disorders; Modality; Modeling; Molecular Biology; Moods; Nature; Nausea; Neurobiology; Nicotine; Nicotine Dependence; Opioid Peptide; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Population; Positive Reinforcements; Prevalence; Productivity; Property; Receptor Signaling; Relapse; Reporting; Rewards; Rodent; Role; Route; Screening procedure; Seizures; Series; Signal Pathway; Sleeplessness; Small Business Technology Transfer Research; Smoke; Smoker; Smoking; Smoking History; Staging; Stress; Stroke; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Agents; Tobacco; Tobacco Dependence; Tobacco use; United States; Work; Xerostomia; addiction; analog; base; chemical property; design; drug discovery; drug market; effective therapy; experience; gastrointestinal; hypocretin; in vivo; inhibitor/antagonist; innovation; interest; knowledge base; negative emotional state; neurochemistry; nicotine replacement; novel; novel therapeutics; orexin 1 receptor; pharmacophore; pre-clinical; receptor; research study; response; scaffold; small molecule; smoking cessation; stable cell line; success; therapy development; varenicline

DESCRIPTION (provided by applicant): Tobacco use is now recognized as the single most responsible cause of avoidable death worldwide representing approximately 10% of all deaths globally. Directly or indirectly, long term tobacco use has been implicated in complex major health disorders such as cancer, stroke, cardiovascular diseases, and mental disorders. In the USA alone, 30% of all cancer deaths and 87% of all lung cancer deaths are reported to be tobacco-use related. Besides the toll on human health, the estimated annual economic burden of tobacco use had reached over $193 billion both in lost productivity and associated health care costs in the USA. Although significant progress has been made towards the understanding and treatment of nicotine dependence, still approximately 21% of the adult population in the United States continues to smoke, and the increase in disease prevalence and health care expenditure has been positively correlated with smoking. In spite of the sustained national effort that has been undertaken to educate, encourage and help tobacco users to quit and abstain from smoking, only a small percentage of smokers manage to relinquish permanently without an interventional agent. The majority of current therapies for smoking cessation such as nicotine replacement therapy, bupropion and varenicline target the positive reinforcement or the pleasurable effects of nicotine. In contrast, there is currently no therapeutic available for the treatment of nicotine addiction that targets the brain stress systems or the negatively reinforced properties of nicotine addiction. In addition, the efficacy of most of these available therapeutic modalities has not been greatly satisfactory, and is further confounded by serious unwanted side effects such as insomnia, dry mouth, seizure, nausea, headache, psychotropic and gastrointestinal upset. Thus it becomes clear that current smoking cessation therapies are inadequate and that there is a significant need to develop therapeutic agents with new mechanisms of action for more effective treatment of tobacco addiction. An abundance of pharmacological and molecular biology data have implicated the significant roles that Orexin-1 (OX-R1) and Corticotropin-releasing factor receptor-1 (CRF-R1) play in the neurobiology of tobacco addiction and relapse. These data also support the convergent and complementary nature of these receptor signaling pathways. It is then logical to envision a therapeutic approach based on a single agent with a dual CRF-R1 and OX-R1 antagonist profile for nicotine addiction. To date, there is no small molecule with a dual antagonist activity on OX-R1 and CRF-R1. Hence, identifying a drug-like dual OX-R1:CRF-R1 antagonist would have great potential for the treatment of tobacco addiction and would represent a significant advancement in the field. Therefore, the specific aim of this Phase 1 STTR proposal is to identify, characterize, and develop a novel, potent (IC50 <1 uM on both OX- R1:CRF-R1) and selective (>10 x fold over OX-R2 and CRF2) antagonist chemical series, from which we will select a candidate with the best overall biological and physical-chemical properties for a Phase 2 STTR in-vivo study for potential use in the treatment of tobacco addiction and relapse. A successful identification of novel and dual OX-R1:CRF-R1 inhibitors with balanced in-vitro profile in this Phase 1 project would allow us to progress to a final lead optimization campaign focused on identifying pre- clinical leads with well-balanced in vivo pharmacokinetics (PK) parameters for key behavioral as well as pharmacological POC studies in rodent addiction and relapse models during a Phase 2 continuing grant. PUBLIC HEALTH RELEVANCE: Directly or indirectly, long term tobacco use has been implicated in causing complex major health disorders such as cancer, stroke, cardiovascular diseases, and mental disorders that result in otherwise avoidable death worldwide. In the USA alone, 30% of all cancer deaths and 87% of all lung cancer deaths are reported to be related to tobacco use. The economic burden of tobacco use due to associated health-care costs and lost productivity has risen to over $193 billion annually in the US alone. Despite interest in quitting smoking, only a small percentage of smokers manage to relinquish permanently without an interventional agent. Unfortunately, the efficacy of most of the available smoking cessation therapeutic modalities has not been satisfactory, and is further confounded by serious unwanted side effects. It is the aim of this project to discover & develop novel therapeutic agents with unique mechanisms of action for more effective treatment of tobacco addiction and relapse.

描述（由申请人提供）：烟草使用现已被认为是全球可避免死亡的最重要原因，约占全球所有死亡的 10%。长期吸烟直接或间接地与复杂的重大健康疾病有关，例如癌症、中风、心血管疾病和精神障碍。据报道，仅在美国，30% 的癌症死亡和 87% 的肺癌死亡与烟草使用有关。除了对人类健康造成的损失之外，在美国，烟草使用造成的生产力损失和相关医疗保健费用估计每年造成的经济负担已超过 1,930 亿美元。尽管在认识和治疗尼古丁依赖方面已经取得了重大进展，但美国仍有约21%的成年人继续吸烟，而且疾病患病率和医疗保健支出的增加与吸烟呈正相关。尽管国家不断努力教育、鼓励和帮助烟草使用者戒烟，但只有一小部分吸烟者能够在没有干预药物的情况下永久戒烟。目前大多数戒烟疗法，如尼古丁替代疗法、安非他酮和伐尼克兰，都是以尼古丁的积极强化或愉悦效果为目标。相比之下，目前还没有针对大脑应激系统或尼古丁成瘾的负面强化特性的尼古丁成瘾治疗方法。此外，大多数这些可用的治疗方式的功效并不十分令人满意，并且还被严重的不良副作用所困扰，例如失眠、口干、癫痫发作、恶心、头痛、精神和胃肠道不适。因此，很明显，当前的戒烟疗法是不够的，并且非常需要开发具有新作用机制的治疗剂以更有效地治疗烟草成瘾。大量的药理学和分子生物学数据表明，Orexin-1 (OX-R1) 和促肾上腺皮质激素释放因子受体-1 (CRF-R1) 在烟草成瘾和复吸的神经生物学中发挥着重要作用。这些数据还支持这些受体信号传导途径的收敛性和互补性。因此，可以合理地设想一种基于具有双重 CRF-R1 和 OX-R1 拮抗剂特征的单一药物来治疗尼古丁成瘾的治疗方法。迄今为止，还没有对OX-R1和CRF-R1具有双重拮抗活性的小分子。因此，鉴定一种类似药物的双重 OX-R1:CRF-R1 拮抗剂对于治疗烟草成瘾具有巨大潜力，并将代表该领域的重大进步。因此，这一阶段 1 STTR 提案的具体目标是识别、表征和开发一种新型、有效（OX-R1:CRF-R1 上的 IC50 <1 uM）和选择性（> 10 倍于 OX-R2 和CRF2）拮抗剂化学系列，我们将从其中选择具有最佳整体生物学和物理化学特性的候选药物，进行 2 期 STTR 体内研究，以潜在用于治疗烟草成瘾和复吸。在此一期项目中成功鉴定出具有平衡体外特征的新型双 OX-R1:CRF-R1 抑制剂将使我们能够开展最终的先导化合物优化活动，重点是识别具有良好体内平衡的临床前先导化合物在第二阶段持续拨款期间，啮齿动物成瘾和复发模型中关键行为和药理学 POC 研究的药代动力学 (PK) 参数。 公共卫生相关性：长期使用烟草直接或间接导致复杂的重大健康疾病，如癌症、中风、心血管疾病和精神障碍，从而导致全世界本来可以避免的死亡。据报道，仅在美国，30% 的癌症死亡和 87% 的肺癌死亡与吸烟有关。仅在美国，由于相关的医疗保健费用和生产力损失，烟草使用造成的经济负担每年就已超过 1,930 亿美元。尽管对戒烟很感兴趣，但只有一小部分吸烟者能够在没有干预药物的情况下永久戒烟。不幸的是，大多数现有的戒烟治疗方式的功效并不令人满意，并且还因严重的不良副作用而变得更加混乱。该项目的目的是发现和开发具有独特作用机制的新型治疗剂，以更有效地治疗烟草成瘾和复吸。