Ethanol Dependence and Kappa Receptor Antagonists

乙醇依赖性和 Kappa 受体拮抗剂

• 批准号: 7612529
• 负责人: Marc Reza Azar
• 金额: $ 11万
• 依托单位: BEHAVIORAL PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612529
• 关键词: Acute; Address; Adverse effects; Affect; Affinity; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animal Testing; Animals; Attenuated; Behavioral Model; Biochemical; Biological Assay; Biological Availability; Biological Products; Cardiovascular Diseases; Cells; Cessation of life; Chemicals; Chronic; Clinical Trials; Data; Dependence; Development; Disease; Dose; Drug Kinetics; Drug abuse; Dynorphins; Ensure; Ethanol; Ethanol dependence; Ethanol toxicity; FDA approved; Family health status; Fetal Alcohol Syndrome; Goals; Healthcare Systems; Heavy Drinking; Hepatotoxicity; Housing; Human; In Vitro; Individual; Injury; Intake; Investigation; Investigational Drugs; Investigational New Drug Application; Lead; Life; Liver diseases; Malignant Neoplasms; Marketing; Measures; Mediating; Mediation; Metabolic; Metabolism; Methodology; Modeling; Modification; Motivation; Naltrexone; Narcotic Antagonists; Opioid; Opioid Receptor; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Population; Preclinical Drug Development; Preparation; Principal Investigator; Procedures; Process; Property; Protein Binding; Public Health; Publishing; Relapse; Reporting; Reproducibility of Results; Research; Rewards; Role; Safety; Self Administration; Series; Site; Societies; Solubility; Source; Staging; System; Testing; Therapeutic; Therapeutic Human Experimentation; Therapeutic Uses; Time; Toxic effect; Toxicology; Vehicle crash; Walkers; Withdrawal; Work; addiction; alcohol effect; alcohol poisoning; analog; base; combat; commercial application; cost; cost efficient; drinking; drug candidate; drug development; drug efficacy; economic impact; endogenous opioids; experience; improved; in vivo; kappa opioid receptors; mu opioid receptors; nalmefene; novel; pre-clinical; preclinical study; preference; problem drinker; programs; public health relevance; receptor; research study; small molecule; vapor

DESCRIPTION (provided by applicant): In the US, alcoholism is a serious disorder that will affect 14% of the population at some point in their lives. 100,000 US citizens will die of alcoholism each year from direct and indirect causes at a cost of $166 billion per year. In addition to contributing to traumatic death and injury (e.g., through car crashes), alcoholism is associated with chronic liver disease, cancers, cardiovascular disease, acute alcohol poisoning (i.e., alcohol toxicity), and fetal alcohol syndrome. Alcoholism is a chronic relapsing disorder characterized by multiple stages and multiple sources of motivation for excessive intake of the drug (i.e., the addiction cycle). The acute effects of ethanol are both reinforcing and rewarding in animal models such as operant self-administration and conditioned place preference. For medications development, several animal models including excessive drinking during dependence have been developed. Strengths of this model are that it represents a critical aspect of construct validity and is reliable. For example, recent work points to this animal model as a sensitive measure of opioid drug efficacy. Naltrexone, a mu-opioid receptor antagonist, is one of few drugs approved by the US FDA for treating alcoholism. However, naltrexone use is associated with dose-dependent hepatotoxic side effects that complicates its use and confounds treatment of alcoholic patients with liver disease. Additional shortcomings include less than desirable duration of action and relatively low bioavailability, gradual diminishing of beneficial effects over time, and possibly, a relatively low affinity for delta and kappa receptors thought to contribute to diminishing the reinforcing effects of drinking alcohol. Nalmefene, a compound closely related to naltrexone, offers promise but has similar drawbacks. Therefore, an important goal of alcoholism therapeutics research remains to identify new and safer compounds that are more effective at suppressing alcohol consumption with reduced toxicity. We have generated novel compounds with enhanced in vivo potency and superior pharmaceutical properties, including greater metabolic stability, that are expected to increase duration of action and decrease hepatotoxicity. The lead compound represents a new class of therapeutic for use in treating alcoholism, and has been selected for advanced preclinical drug development. The Aims of Phase I work are: 1) Re-synthesize the lead compound 2) Evaluate the lead compound in an alcohol-dependent animal model informative in studies of alcohol consumption and 3) Summarize the data prior to advanced preclinical IND-enabling studies. The Aims of Phase II include: 1) Refine the lead compound in a second alcohol-dependent animal model of excess drinking, 2) Fully characterize the biopharmaceutical properties of the lead compound, 3) Do IND enabling studies of the compound, and 4) Validate the medications development of the compound for clinical trials of human alcohol cessation. Completion of the proposed Fast Track Aims will show the efficacy of the lead compound in anti-alcoholism effects and afford a novel pharmacological agent for eventual pharmacotherapy in human clinical trials of alcoholism. PUBLIC HEALTH RELEVANCE: The need for potent, orally active medications to address diseases of alcohol and drug abuse is immense. Development of the lead compound affording a long-acting anti-alcoholism agent that possesses an improved side effect profile compared to drugs currently on the market will provide a therapeutic that is currently not available. The potential commercial application of the work is that the research could lead to a "blockbuster" drug product.

描述(申请人提供)：在美国，酒精中毒是一种严重的疾病，会在他们一生中的某个时候影响14%的人口。每年将有10万名美国公民死于直接和间接原因的酒精中毒，每年的损失为1660亿美元。除了造成创伤性死亡和受伤(例如，车祸)外，酒精中毒还与慢性肝病、癌症、心血管疾病、急性酒精中毒(即酒精中毒)和胎儿酒精综合征有关。酒精中毒是一种慢性复发性障碍，其特征是多阶段和多来源的过量吸食药物(即成瘾循环)。酒精的急性效应在动物模型中既强化又有回报，例如操作性自我给药和条件性位置偏爱。在药物开发方面，已经开发了几种动物模型，包括在依赖期间过度饮酒。这个模型的优点是它代表了结构效度的一个关键方面，并且是可靠的。例如，最近的研究指出，这种动物模型是衡量阿片类药物疗效的敏感指标。纳曲酮是一种u阿片受体拮抗剂，是美国FDA批准的为数不多的治疗酒精中毒的药物之一。然而，纳曲酮的使用与剂量依赖的肝毒性副作用有关，这使其使用复杂化，并混淆了酒精性肝病患者的治疗。其他缺点包括作用时间短，生物利用度相对较低，有益效果随着时间的推移逐渐减弱，可能与被认为有助于减弱饮酒增强效果的Delta和kappa受体亲和力相对较低。纳美芬是一种与纳曲酮关系密切的化合物，它有希望，但也有类似的缺点。因此，酒精中毒治疗研究的一个重要目标仍然是寻找新的、更安全的化合物，这些化合物在降低毒性的同时更有效地抑制酒精消费。我们已经产生了具有增强的体内效力和优异的药学特性的新型化合物，包括更好的代谢稳定性，预计将延长作用时间并降低肝脏毒性。该先导化合物代表了用于治疗酒精中毒的一种新的治疗性药物，并已被选为先进的临床前药物开发。第一阶段工作的目标是：1)重新合成先导化合物，2)在酒精依赖动物模型中评估先导化合物，在酒精消费研究中提供信息，3)在高级临床前使能研究之前总结数据。第二阶段的目标包括：1)在第二个过度饮酒的酒精依赖动物模型中提炼先导化合物，2)充分表征先导化合物的生物药学特性，3)对该化合物进行IND研究，以及4)验证该化合物的药物开发，用于人类戒酒的临床试验。拟议的快速通道目标的完成将显示该先导化合物在抗酒精中毒方面的功效，并为人类酒精中毒临床试验的最终药物治疗提供一种新的药理制剂。与公共卫生相关：迫切需要有效的口服活性药物来解决酒精和药物滥用的疾病。与目前市场上的药物相比，提供具有改善副作用的长效解酒药剂的先导化合物的开发将提供目前无法获得的治疗方法。这项工作的潜在商业应用是，这项研究可能会导致一种“重磅炸弹”的药物产品。