Preclinical Development of Selective PKC_epsilon Inhibitors to Treat Alcoholism

选择性 PKC_epsilon 抑制剂治疗酒精中毒的临床前开发

• 批准号: 7924910
• 负责人: Jay Jie Qiang Wu
• 金额: $ 10万
• 依托单位: VM DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924910
• 关键词: Abdominal Pain; Abstinence; Acetaldehyde; Adverse effects; Affect; Aftercare; Alcohol abuse; Alcohol consumption; Alcoholic Neuropathy; Alcoholism; Alcohols; Animal Disease Models; Anxiety; Biological Assay; Blood - brain barrier anatomy; Cardiac; Clinical; Communicable Diseases; Computer Simulation; Data; Development; Diarrhea; Dizziness; Drug Kinetics; Drug Metabolic Detoxication; Drug abuse; Effectiveness; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Exanthema; Exhibits; Experimental Animal Model; Fatigue; Flushing; Frequencies; Future; Heavy Drinking; Human; Hypotension; Injury; Intervention; Lead; Legal; Libido; Liver; Maintenance; Medical; Modification; Molecular; Mus; N-Methylaspartate; Naltrexone; Nausea; Nervous system structure; Neurosciences; Ondansetron; Opioid Receptor; Pain; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phosphotransferases; Population; Pre-Clinical Model; Property; Psychotherapy; Public Health; Rattus; Rehabilitation therapy; Relapse; Reporting; Research; Risk; Rodent; Sedation procedure; Self Administration; Small Business Innovation Research Grant; Specificity; Structure; Structure-Activity Relationship; Testing; Time; Toxic effect; United States; Wages; Water; Work; acamprosate; alcohol craving; alcohol effect; alcohol use disorder; aldehyde dehydrogenases; base; computational chemistry; cost; drinking; drug candidate; effective therapy; improved; in vivo; inhibitor/antagonist; interest; meetings; neoplastic; novel; pre-clinical; protein kinase C epsilon; psychosocial; receptor; research and development; scaffold; small molecule; topiramate

DESCRIPTION (provided by applicant): Alcoholism and alcohol abuse are the most common forms of drug abuse and effect about 8% of the U.S. population at a cost of approximately $184 billion a year. Current treatment generally consists of psychosocial therapies aimed at rehabilitation and reducing alcohol-associated problems and pharmacotherapy with a limited number of approved drugs. While current treatment can be effective in reducing alcohol consumption, it is estimated that 40-70% of patients return to excessive drinking within a year after treatment. This is partly due to the modest effectiveness of currently approved medications and their side effects, which contribute to poor compliance with their use. Clearly, there is a need to develop more effective drugs. A large body of preclinical data available through studies of mice deficient in PKC_epsilon and rats treated with a peptide inhibitor of PKC_epsilon provides a strong case for development of PKC_epsilon inhibitors to reduce alcohol self-administration and pain associated with alcoholic polyneuropathy. In addition, evidence indicates that PKC_epsilon inhibitors could be useful for the treatment of anxiety, which is commonly associated with alcoholism and may contribute to excessive drinking. This proposal is focused on the preclinical development of a novel class of small organic compounds that act as inhibitors of the enzyme PKC_epsilon. Currently, there are no selective inhibitors of PKC_epsilon that can be administered systemically and cross the blood-brain barrier. Based on combined multi-property computational modeling and wet-lab verification in our Phase I SBIR study, a water soluble small organic molecule, VMD-C620 was identified as an effective and relatively selective "allosteric" PKC_epsilon inhibitor acting reversibly and noncompetitively with ATP and substrate. VMD-C620 was also shown to be efficacious in an experimental animal model of alcoholic polyneuropathy and exhibited high specificity when assayed against related kinases, including the highly related PKC_epsilon. Its distinctive molecular scaffold is very amenable to modification and optimization by medicinal and computational chemistries. These unique properties make VMD-C620 an excellent candidate to be further derived, optimized and developed for the potential treatment of alcohol use disorders. The project proposed here is to develop more potent derivatives of VMD-C620 and study them in preclinical pharmacokinetic and animal disease models relevant to alcohol use disorders. This work will form the basis for future studies, which will complete preclinical development to allow testing of a novel PKC_epsilon inhibitor in humans as a new and improved agent for treatment of alcohol use disorders.

描述(申请人提供)：酗酒和酗酒是最常见的药物滥用形式，每年造成约1840亿美元的损失，影响约8%的美国人口。目前的治疗一般包括旨在康复和减少酒精相关问题的心理社会治疗，以及使用数量有限的批准药物的药物治疗。虽然目前的治疗方法在减少饮酒方面是有效的，但据估计，40%-70%的患者在治疗后一年内恢复过度饮酒。这在一定程度上是由于目前批准的药物效果不佳及其副作用，导致其使用依从性较差。显然，有必要开发更有效的药物。通过对PKC_epsilon缺陷小鼠和使用PKC_epsilon的多肽抑制剂治疗的大鼠的研究，获得了大量的临床前数据，为开发PKC_epsilon抑制剂以减少酒精自我给药和与酒精性多发性神经病相关的疼痛提供了强有力的证据。此外，有证据表明，PKC_epsilon抑制剂可能对治疗焦虑有用，焦虑通常与酒精中毒有关，并可能导致过度饮酒。这项建议集中在一类新的小分子有机化合物的临床前开发，这些化合物可以作为PKC_epsilon酶的抑制剂。目前，还没有选择性的PKC_epsilon抑制剂可以全身给药并通过血脑屏障。在我们的第一阶段SBIR研究中，基于多性质计算模型和湿法实验室验证相结合的方法，VMD-C620被确定为一种有效的、相对选择性的“变构”PKC_epsilon抑制剂，它与ATP和底物可逆地、非竞争性地作用。在酒精性多发性神经病的实验动物模型中，VMD-C620也被证明是有效的，当检测到相关的激酶，包括高度相关的PKC_epsilon时，VMD-C620显示出高度的特异性。其独特的分子支架非常容易被药物和计算化学修改和优化。这些独特的特性使VMD-C620成为进一步衍生、优化和开发潜在治疗酒精使用障碍的极佳候选药物。这里提出的项目是开发更有效的VMD-C620衍生物，并在与酒精使用障碍相关的临床前药代动力学和动物疾病模型中研究它们。这项工作将为未来的研究奠定基础，该研究将完成临床前开发，以便能够在人类身上测试一种新型的PKC_epsilon抑制剂，作为一种治疗酒精使用障碍的新的改进试剂。