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

说明(申请人提供)：烟草使用现在被认为是全球可避免死亡的唯一最主要原因，约占全球所有死亡人数的10%。直接或间接地，长期吸烟与复杂的重大健康疾病有关，如癌症、中风、心血管疾病和精神障碍。据报道，仅在美国，30%的癌症死亡病例和87%的肺癌死亡病例都与烟草使用有关。除了对人类健康造成的损失外，在美国，烟草使用每年造成的经济负担估计已超过1930亿美元，包括生产力损失和相关的医疗保健费用。尽管在了解和治疗尼古丁依赖方面取得了重大进展，但美国仍有约21%的成年人口继续吸烟，疾病患病率和医疗支出的增加与吸烟呈正相关。尽管在全国范围内持续努力教育、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干预因素的情况下永久戒烟。目前的大多数戒烟疗法，如尼古丁替代疗法、安非他酮和瓦伦尼克林，都是针对尼古丁的积极强化或愉悦效果。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的治疗方法。此外，大多数现有治疗方法的疗效都不太令人满意，并因严重的不良副作用而进一步混乱，如失眠、口干、癫痫、恶心、头痛、精神药物和胃肠道不适。因此，很明显，目前的戒烟疗法是不够的，迫切需要开发具有新作用机制的治疗剂，以便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，增食欲素-1(OX-R1)和促肾上腺皮质激素释放因子受体-1(CRF-R1)在烟草成瘾和复发的神经生物学中发挥着重要作用。这些数据也支持这些受体信号通路的汇聚性和互补性。因此，设想一种基于具有双重CRF-R1和OX-R1拮抗剂的单一药物的尼古丁成瘾治疗方法是合乎逻辑的。到目前为止，还没有对OX-R1和CRF-R1具有双重拮抗作用的小分子。因此，找出一种类药物的双重OX-R1：CRF-R1拮抗剂将具有治疗烟草成瘾的巨大潜力，并将是该领域的重大进展。因此，这个第一阶段STTR提案的具体目的是确定、表征和开发一种新的、有效的(在OX-R1：CRF-R1上的IC50和1um)和选择性的(OX-R2和CRF2的10倍)拮抗剂化学系列，我们将从该化学系列中选择具有最好的综合生物学和物理化学特性的候选者，用于第二阶段STTR体内研究，潜在地用于烟草成瘾和复发的治疗。在这个第一阶段的项目中，成功识别出体外平衡的新型和双重OX-R1：CRF-R1抑制剂，将使我们能够继续进行最终的线索优化活动，重点是在第二阶段持续资助期间，为啮齿动物成瘾和复发模型的关键行为和药理学POC研究确定具有良好平衡的体内药代动力学(PK)参数的临床前线索。 与公共卫生相关：直接或间接地，长期吸烟导致了复杂的重大健康疾病，如癌症、中风、心血管疾病和精神障碍，这些疾病导致了全球范围内原本可以避免的死亡。据报道，仅在美国，30%的癌症死亡病例和87%的肺癌死亡病例都与吸烟有关。仅在美国，由于相关的医疗保健成本和生产力损失而造成的烟草使用的经济负担就已上升到每年超过1930亿美元。尽管有戒烟的兴趣，但只有一小部分吸烟者在没有干预因素的情况下永久戒烟。不幸的是，大多数可用的戒烟治疗方法的效果并不令人满意，而且还被严重的不良副作用进一步混淆。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发。

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.