Ethanol Dependence and Kappa Receptor Antagonists

乙醇依赖性和 Kappa 受体拮抗剂

• 批准号: 8135955
• 负责人: Marc Reza Azar
• 金额: $ 38.63万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135955
• 关键词: Acute; Address; Adverse effects; Affect; Affinity; Alcohol abuse; 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; Health; Healthcare Systems; Heavy Drinking; Hepatotoxicity; Housing; Human; In Vitro; Individual; Injury; Intake; Investigation; Investigational Drugs; Investigational New Drug Application; Lead; 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; delta opioid receptor; 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; 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（由申请人提供）：在美国，酗酒是一种严重的疾病，将影响14%的人口在他们生命中的某个时候。每年将有10万美国公民因直接和间接原因死于酒精中毒，每年造成1660亿美元的损失。除了造成创伤性死亡和伤害（例如，通过车祸），酒精中毒与慢性肝病、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。酒精中毒是一种慢性复发性疾病，其特征在于多个阶段和多个过度摄入药物的动机来源（即，成瘾循环）。在操作性自我管理和条件性位置偏爱等动物模型中，乙醇的急性效应既有强化作用，又有奖励作用。在药物开发方面，已经开发了几种动物模型，包括依赖期间过度饮酒。该模型的优点在于它代表了结构效度的一个关键方面，并且是可靠的。例如，最近的工作指出这种动物模型是阿片类药物疗效的敏感指标。纳洛酮是一种μ阿片受体拮抗剂，是美国FDA批准用于治疗酒精中毒的少数药物之一。然而，纳洛酮的使用与剂量依赖性肝毒性副作用有关，这使其使用复杂化，并混淆了患有肝病的酒精患者的治疗。另外的缺点包括小于期望的作用持续时间和相对较低的生物利用度，有益效果随时间逐渐减少，以及可能的，对δ和κ受体的相对较低的亲和力被认为有助于减少饮酒的增强效果。纳美芬，一种与纳洛酮密切相关的化合物，提供了希望，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确定新的和更安全的化合物，更有效地抑制酒精消费，降低毒性。我们已经产生了具有增强的体内效力和上级药学性质的新型化合物，包括更大的代谢稳定性，预期其可增加作用持续时间并降低肝毒性。先导化合物代表了一种用于治疗酒精中毒的新型治疗药物，并已被选择用于先进的临床前药物开发。I期工作的目的是：1）重新合成先导化合物，2）在酒精依赖动物模型中评价先导化合物，为酒精消耗研究提供信息，3）在高级临床前IND使能研究之前总结数据。II期的目的包括：1）在过量饮酒的第二个酒精依赖动物模型中精制先导化合物，2）充分表征先导化合物的生物制药特性，3）进行化合物的IND使能研究，以及4）验证化合物用于人类戒酒临床试验的药物开发。完成拟议的快速通道目标将显示先导化合物在抗酒精中毒作用中的功效，并为酒精中毒的人类临床试验中的最终药物治疗提供新型药理学药剂。公共卫生相关性：对强效口服活性药物的需求巨大，以解决酒精和药物滥用疾病。与目前市场上的药物相比，开发提供具有改善的副作用特征的长效戒酒剂的先导化合物将提供目前不可用的治疗剂。这项工作的潜在商业应用是，这项研究可能导致一种“重磅炸弹”药物产品。