Preclinical Development of Selective PKC_epsilon Inhibitors to Treat Alcoholism

描述(由申请人提供)：酗酒和酗酒(酒精使用障碍)是严重的公共卫生问题，是最大的公共卫生问题之一。仅在美国，酒精使用障碍就影响了大约1400万人，每年因工资损失、相关伤害以及肝脏、心脏、肿瘤或传染病造成的法律和医疗费用损失约1840亿美元。尽管已经开发出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显然超过50%，即使在戒酒数十年后也可能发生。到目前为止，只有三种药物在美国被批准用于治疗：双呋喃、纳曲酮和氨基己酸酯。双硫仑对积极性高、依从性高的患者的短期治疗很有用，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，它有严重的肝脏、心脏和神经系统毒性的风险。对于引起各种副作用的纳曲酮和氨基己酸酯，依从性普遍较低，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”神经生物学理论来解释酒精使用障碍的基本机制，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，而且一些不同靶点的不同药物已经进行了测试。目前的提议集中在开发一种新的口服化合物，作为蛋白激酶C epsilon(PKCE)的异构体特异性抑制剂，已被证明是治疗酒精使用障碍的理想靶点。这项SBIR第二阶段竞争性更新研究计划的总体目标是推进我们先前第二阶段计划的积极成果，通过向FDA申请用于治疗酒精使用障碍的研究性新药(IND)，开发第一种口服和中枢神经系统活性和异构体选择性的PKCE抑制剂VMD-2202。VMD-2202口服有效，在不影响水摄入量的情况下，减少已建立的动物模型中过量的酒精摄入量。它具有合理的体内安全性，没有镇静或运动不协调，这是许多中枢神经系统药物中常见的一种中枢神经系统副作用。我们现在通过IND向FDA提交一个为期三年的临床前药物开发项目，根据NIH SBIR第二阶段竞争性更新奖在NIAAA。在这项提案的第一年，我们打算通过一组已建立的临床前啮齿动物模型进一步测试VMD-2202在酒精使用障碍的不同阶段的治疗潜力。同时，我们将对基于VMD-2202的新型化学支架进行进一步的铅优化，选择另一种铅类似物作为备份实体。在第二年和第三年，我们将对第一年提前的一个选定的开发候选进行IND使能研究，包括对两个动物物种的安全性和药代动力学概况、GMP制造和GLP安全药理学和毒理学研究，这是向FDA申请IND所必需的。在这个赠款项目的第三年结束时，我们将编写和组装IND包并将其提交给FDA。如果FDA接受IND申请，我们将很快开始第一阶段的人体临床试验。 公共卫生相关性：酗酒和酗酒(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，酒精使用障碍就影响了大约1400万人，由于工资、法律和医疗费用的损失，每年造成的损失约为1840亿美元。到目前为止，只有三种药物在美国被批准用于治疗：双呋喃、纳曲酮和氨基己酸酯。这些批准的药物都存在严重的副作用和患者依从性低的问题。这项SBIR第二阶段竞争性更新研究计划的总体目标是通过向FDA申请治疗酒精使用障碍的研究性新药(IND)，使首个口服和中枢神经系统活性和异构体选择性的PKCepsilon抑制剂能够在临床前开发。在这个赠款项目的第三年结束时，我们将编写和组装IND包并将其提交给FDA。如果FDA接受IND申请，我们将很快开始第一阶段的人体临床试验。

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.