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

描述（由申请人提供）：烟草使用现在被认为是全世界可避免死亡的最主要原因，约占全球所有死亡人数的10%。长期使用烟草直接或间接地与癌症、中风、心血管疾病和精神障碍等复杂的重大健康障碍有关。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损害外，据估计，在美国，烟草使用每年造成的生产力损失和相关医疗保健费用的经济负担已超过1930亿美元。尽管在了解和治疗尼古丁依赖方面已经取得了重大进展，但在美国仍有大约21%的成年人继续吸烟，而且疾病患病率和卫生保健支出的增加与吸烟呈正相关。尽管在教育、鼓励和帮助烟草使用者戒烟和不吸烟方面作出了持续的国家努力，但只有一小部分吸烟者能够在没有干预剂的情况下永久戒烟。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治疗方法。此外，大多数现有的治疗方式的疗效都不太令人满意，而且还存在严重的副作用，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，目前的戒烟疗法是不够的，迫切需要开发具有新的作用机制的治疗剂，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，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起着重要作用。这些数据也支持这些受体信号通路的收敛性和互补性。因此，设想一种基于具有双重CRF-R1和OX-R1拮抗剂的单一药物治疗尼古丁成瘾的方法是合乎逻辑的。迄今为止，还没有小分子对OX-R1和CRF-R1具有双重拮抗剂活性。因此，确定一种类似于药物的OX-R1:CRF-R1双拮抗剂将具有治疗烟草成瘾的巨大潜力，并将代表该领域的重大进展。因此，这项1期STTR提案的具体目标是确定、表征和开发一种新的、有效的（对OX- R1:CRF-R1的IC50 <1 uM）和选择性的（比OX- r2和CRF2的IC50 < 10倍）拮抗剂化学系列，从中我们将选择一种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，用于治疗烟草成瘾和复发。在这个第一阶段项目中，成功鉴定出具有平衡体外特征的新型和双重OX-R1:CRF-R1抑制剂，将使我们能够进入最终的先导物优化活动，重点是在第二阶段持续拨款期间，确定具有平衡的体内药代动力学（PK）参数的临床前先导物，用于啮齿动物成瘾和复发模型的关键行为和药理POC研究。

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.