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

基本信息

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
项目类别：
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

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

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项目摘要

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）：烟草使用现在被认为是全球可避免死亡的最负责任的唯一原因，约占全球所有死亡人数的10％。直接或间接的，长期使用的烟草使用与复杂的主要健康疾病有关，例如癌症，中风，心血管疾病和精神疾病。仅在美国，据报道，所有癌症死亡中有30％和87％的肺癌死亡与烟草使用有关。除了对人类健康的损失外，美国烟草使用的年度经济负担在美国的生产力损失和相关的医疗保健费用都达到了超过1,930亿美元。尽管在理解和治疗尼古丁依赖性方面取得了重大进展，但美国仍有大约21％的成年人口继续吸烟，疾病患病率和医疗保健支出的增加与吸烟呈正相关。尽管已经采取了持续的全国性努力来教育，鼓励和帮助烟草使用者戒烟和戒烟，但只有一小部分吸烟者能够在没有介入剂的情况下永久放弃。当前大多数用于戒烟的疗法，例如尼古丁替代疗法，安非他酮和varenicline靶向阳性增强或尼古丁的愉悦作用。相比之下，目前尚无治疗方法可用于靶向脑应力系统或尼古丁成瘾的负强化特性的尼古丁成瘾。此外，大多数这些可用的治疗方式的功效并不令人满意，并且由于严重的不良副作用（例如失眠，口干，癫痫发作，恶心，头痛，精神和胃肠道疾病）而进一步混淆。因此，很明显，目前的戒烟疗法不足，并且需要开发具有新的作用机理的治疗剂，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暗示了Orexin-1（OX-R1）和皮质激素释放因子受体受体1（CRF-R1）在烟草成瘾和复发的神经生物学中起的重要作用。这些数据还支持这些受体信号通路的收敛性和互补性。然后，基于具有双CRF-R1和OX-R1拮抗剂的单个药物来设想一种治疗方法，用于尼古丁成瘾。迄今为止，没有小分子在OX-R1和CRF-R1上具有双重拮抗剂活性。因此，鉴定出类似药物的双OX-R1：CRF-R1拮抗剂将具有巨大的烟草成瘾治疗潜力，并代表该领域的显着进步。因此，该阶段1 STTR建议的具体目的是识别，表征和发展一种新颖的，有效的（在OX-R1：CRF-R1上的IC50 <1 um）和选择性（OX-R2和CRF2上的> 10 x折叠（> 10 x折叠）拮抗剂化学系列，我们将从该系列中选择一个候选者，以对候选者进行最佳的生物学和物理化构图和物理化的构图，以实现对阶段2阶段2 StTRTR的效果研究，并从中选择Inter Intry Intr In-Viv strtr in-Viv strtr in-VIV in-Viv in-viv strtr in-Viv in-viv strtr in-Viv in-vo in-Viv in-vo复发。在此阶段1项目中，成功识别具有平衡体外概况的新颖和双OX-R1：CRF-R1抑制剂将使我们能够进入最终的潜在客户优化运动，重点是确定具有良好平衡的Vivo Pharmacacokinetics（PK）参数（PK）参数的临床前导，以进行关键行为和药物学批准，并在摩根式的相关模型中进行一项阶段批准。公共卫生相关性：直接或间接的，长期使用的烟草使用涉及引起复杂的重大健康疾病，例如癌症，中风，心血管疾病和精神疾病，导致全球范围内可避免的死亡。仅在美国，据报道，所有癌症死亡中有30％和87％的肺癌死亡与烟草使用有关。仅在美国，由于相关的医疗费用和生产率降低，烟草使用的经济负担每年增加到超过1930亿美元。尽管有兴趣戒烟，但只有一小部分吸烟者能在没有介入剂的情况下永久放弃。不幸的是，大多数可用的戒烟治疗方式的功效并不令人满意，并且由于严重的不必要的副作用而进一步混淆。该项目的目的是发现和开发具有独特作用机理的新型治疗剂，以更有效地治疗烟草成瘾和复发。