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: 8126708
• 负责人: Jay Jie Qiang Wu
• 金额: $ 47.39万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126708
• 关键词: Abnormal coordination; Abstinence; Adverse effects; Affect; Alcohol abuse; Alcoholism; Alcohols; Animal Model; Animals; Award; Back; Bioavailable; Blood Pressure; Brain; Cardiac; Cardiovascular system; Chemicals; Clinical; Clinical Trials; Communicable Diseases; Development; Drug Formulations; Drug Kinetics; Drug Packaging; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Evaluation; Generations; Government; Grant; Heart Rate; Heavy Drinking; Human; Injury; Investigational Drugs; Investigational New Drug Application; Ion Channel; Lead; Legal; Liver; Medical; Metabolism; Molecular Target; Motor; Mus; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Nervous system structure; Neurobiology; Oral; Patients; Persons; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phosphotransferases; Preclinical Drug Development; Protein Isoforms; Public Health; Rattus; Relapse; Research; Risk; Rodent Model; Safety; Sedation procedure; Small Business Innovation Research Grant; Staging; Testing; Therapeutic; Toxic effect; Toxicology; United States; United States National Institutes of Health; Wages; Water consumption; Writing; acamprosate; alcohol use disorder; alcoholism therapy; analog; base; chronic constriction injury; compliance behavior; cost; in vivo; inhibitor/antagonist; kinase inhibitor; method development; neoplastic; novel; painful neuropathy; pre-clinical; programs; protein kinase C epsilon; psychosocial; scaffold; scale up; small molecule; theories

DESCRIPTION (provided by applicant): Alcohol abuse and alcoholism (alcohol use disorders) are significant public health issues and represent one of the largest public health problems. In the United States alone, alcohol use disorders affect about 14 million people, costing approximately $184 billion a year due to lost wages, legal and medical costs from associated injuries and liver, cardiac, neoplastic, or infectious diseases. Even though elaborate psychosocial and psychotherapeutic approaches for the treatment of alcoholism have been developed, relapse rates after long- term treatment of alcoholism clearly exceed 50% and may occur even after decades of abstinence. So far, only three drugs have been approved for treatment in the United States: disulfuram, naltrexone and acamprosate. Disulfuram is useful for the short-term treatment of highly motivated and compliant patients, but there is no evidence it is effective in long-term therapy and it carries a risk of significant liver, cardiac, and nervous system toxicity if taken with alcohol. For both naltrexone and acamprosate, which cause a variety of side effects, compliance is generally low, with only about half of patients completing treatment with either drug. Clearly, there is an unmet need to develop more effective compounds with novel molecular targets due to lack of single 'unifying' neurobiological theory to explain basic mechanisms of alcohol use disorders and, some different drugs with different targets have been tested. The current proposal is focused on the development of a novel oral compound that acts as isoform specific inhibitor of the enzyme protein kinase C epsilon (PKCe), which has been demonstrated an ideal target for alcohol use disorders. The overall objective of this SBIR Phase II Competing Renewal research plan is to advance the positive results of our prior Phase II program to enable development of the first oral- and CNS-active and isoform-selective PKCe inhibitor, VMD-2202 through an Investigational New Drug (IND) application to the FDA for the treatment of alcohol use disorders. VMD-2202 is orally effective reducing excessive alcohol intake in established animal model without affecting water intake. It has reasonable in vivo safety profile without sedation or motor incoordination, a CNS side effect often seen in many CNS drugs. We now propose a three-year preclinical drug development project through IND submission to the FDA, under NIH SBIR Phase II Competing Renewal Awards at NIAAA. In the first year of this proposal, we intend to further test therapeutic potential of VMD-2202 in various phases of alcohol uses disorders with a battery of established preclinical rodent models. In parallel, we will perform further lead optimization on the VMD-2202-based novel chemical scaffold to select another lead analog compound as the back-up entity. In the second and third year, we will conduct IND-enabling studies for one chosen development candidate advanced from the first year, including evaluation of the safety and pharmacokinetic profile, GMP manufacture and GLP safety pharmacology and toxicology studies in two animal species, which are necessary for an IND application to the FDA. At the end of the third year of this grant project, we will write and assemble an IND package and submit it to the FDA. If the FDA accepts the IND application, we will shortly thereafter begin the Phase I human clinical trials. PUBLIC HEALTH RELEVANCE: Alcohol abuse and alcoholism (alcohol use disorders) are significant public health issues and represent one of the largest public health problems. In the United States alone, alcohol use disorders affect about 14 million people, costing approximately $184 billion a year due to lost wages, legal and medical costs. So far, only three drugs have been approved for treatment in the United States: disulfuram, naltrexone and acamprosate. These approved drugs all suffer from significant side effects and low patients compliance. The overall objective of this SBIR Phase II Competing Renewal research plan is to enable preclinical development of the first oral- and CNS-active and isoform-selective PKCepsilon inhibitor through an Investigational New Drug (IND) application to the FDA for the treatment of alcohol use disorders. At the end of the third year of this grant project, we will write and assemble an IND package and submit it to the FDA. If the FDA accepts the IND application, we will shortly thereafter begin the Phase I human clinical trials.

描述（由申请人提供）：酒精滥用和酒精中毒（酒精使用障碍）是重大的公共卫生问题，是最大的公共卫生问题之一。仅在美国，酒精使用障碍影响约1400万人，由于相关损伤和肝脏、心脏、肿瘤或传染病造成的工资损失、法律的和医疗费用，每年花费约1840亿美元。尽管已经开发了用于治疗酒精中毒的复杂的心理社会和心理治疗方法，但长期治疗酒精中毒后的复发率明显超过50%，并且甚至在数十年的戒酒后也可能发生。到目前为止，只有三种药物在美国被批准用于治疗：双硫仑，纳洛酮和阿坎酸。双磺草胺可用于高度积极性和依从性患者的短期治疗，但没有证据表明它在长期治疗中有效，如果与酒精一起服用，它会带来显著的肝脏，心脏和神经系统毒性的风险。对于纳洛酮和阿坎酸这两种会引起各种副作用的药物，依从性通常很低，只有大约一半的患者完成了这两种药物的治疗。显然，由于缺乏单一的“统一的”神经生物学理论来解释酒精使用障碍的基本机制，因此开发具有新分子靶点的更有效的化合物的需求尚未得到满足，并且已经测试了具有不同靶点的一些不同药物。目前的建议是集中在开发一种新型的口服化合物，作为酶蛋白激酶C β（PKCe）的亚型特异性抑制剂，这已被证明是酒精使用障碍的理想目标。该SBIR II期竞争性更新研究计划的总体目标是推进我们先前II期计划的积极成果，以通过向FDA申请用于治疗酒精使用障碍的研究性新药（IND），开发第一种口服和CNS活性和亚型选择性PKCe抑制剂VMD-2202。VMD-2202在已建立的动物模型中口服可有效减少过量酒精摄入，而不影响水摄入量。它具有合理的体内安全性，没有镇静或运动不协调，这是许多CNS药物中常见的CNS副作用。我们现在提出了一个为期三年的临床前药物开发项目，通过IND提交给FDA，根据NIH SBIR第二阶段竞争更新奖在NIAAA。在该提案的第一年，我们打算用一系列已建立的临床前啮齿动物模型进一步测试VMD-2202在酒精使用障碍的各个阶段的治疗潜力。同时，我们将对基于VMD-2202的新型化学支架进行进一步的先导优化，以选择另一种先导类似物化合物作为备用实体。在第二年和第三年，我们将对从第一年开始的一个选定的开发候选药物进行IND使能研究，包括在两种动物种属中评价安全性和药代动力学特征、GMP生产和GLP安全药理学和毒理学研究，这是向FDA提交IND申请所必需的。在这个资助项目的第三年年底，我们将编写和组装IND包，并提交给FDA。如果FDA接受IND申请，我们将在此后不久开始I期人体临床试验。 公共卫生相关性：酒精滥用和酒精中毒（酒精使用障碍）是重大的公共卫生问题，是最大的公共卫生问题之一。仅在美国，酒精使用障碍影响约1400万人，由于工资损失、法律的和医疗费用，每年造成约1840亿美元的损失。到目前为止，只有三种药物在美国被批准用于治疗：双硫仑，纳洛酮和阿坎酸。这些批准的药物都有明显的副作用和低患者依从性。该SBIR II期竞争性更新研究计划的总体目标是通过向FDA提交的用于治疗酒精使用障碍的研究性新药（IND）申请，实现第一种口服和CNS活性和亚型选择性PKC 3抑制剂的临床前开发。在这个资助项目的第三年年底，我们将编写和组装IND包，并提交给FDA。如果FDA接受IND申请，我们将在此后不久开始I期人体临床试验。