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: 7226037
• 负责人: Jay Jie Qiang Wu
• 金额: $ 49.83万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226037
• 关键词: Abdominal Pain; Abstinence; Acetaldehyde; Adverse effects; Affect; Aftercare; Alcohol consumption; Alcoholic Neuropathy; Alcoholism; Alcohols; Aldehyde dehydrogenase (NAD+); Animal Disease Models; Anxiety; Biological Assay; Blood - brain barrier anatomy; Cardiac; Class; 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; Numbers; 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 Funding Mechanisms; Small Business Innovation Research Grant; Specificity; Standards of Weights and Measures; Structure; Structure-Activity Relationship; Testing; Time; Toxic effect; United States; Wages; Water; Work; acamprosate; alcohol craving; alcohol effect; alcohol use disorder; alcoholism/alcohol abuse; aldehyde dehydrogenases; base; computational chemistry; cost; desire; drinking; improved; in vivo; inhibitor/antagonist; interest; 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（由申请人提供）：酗酒和酗酒是最常见的药物滥用形式，影响约 8% 的美国人口，每年造成约 1,840 亿美元的损失。目前的治疗通常包括旨在康复和减少酒精相关问题的心理社会疗法以及使用有限数量的批准药物的药物疗法。虽然目前的治疗可以有效减少饮酒量，但估计 40-70% 的患者在治疗后一年内会再次过度饮酒。部分原因是目前批准的药物疗效有限，且有副作用，导致使用依从性较差。显然，需要开发更有效的药物。通过对缺乏 PKC_epsilon 的小鼠和用 PKC_epsilon 肽抑制剂治疗的大鼠进行研究获得的大量临床前数据为开发 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理由。此外，有证据表明 PKC_epsilon 抑制剂可用于治疗焦虑症，焦虑症通常与酗酒有关，并可能导致过度饮酒。该提案的重点是一类新型小有机化合物的临床前开发，这些化合物充当酶 PKC_epsilon 的抑制剂。目前，还没有可以全身给药并穿过血脑屏障的选择性 PKC_epsilon 抑制剂。基于我们 I 期 SBIR 研究中结合的多属性计算模型和湿实验室验证，一种水溶性小有机分子 VMD-C620 被确定为一种有效且相对选择性的“变构”PKC_epsilon 抑制剂，与 ATP 和底物可逆且非竞争性发挥作用。 VMD-C620 在酒精性多发性神经病的实验动物模型中也被证明是有效的，并且在针对相关激酶（包括高度相关的 PKC_epsilon）进行检测时表现出高度特异性。其独特的分子支架非常适合通过药物和计算化学进行修改和优化。这些独特的特性使 VMD-C620 成为进一步衍生、优化和开发的优秀候选药物，用于潜在的酒精使用障碍治疗。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，未来的研究将完成临床前开发，以允许在人体中测试新型 PKC_epsilon 抑制剂，作为治疗酒精使用障碍的新型改良药物。