Development of novel pharmacotherapies for AUD

项目摘要 这项提议的总体目标是用一种新的作用模式(MOA)来表征一种先导化合物 在酒精使用障碍的临床前模型中减少与压力和依赖相关的饮酒 (澳元)。澳元是美国的一个主要问题，每年约有13.9%的成年人达到澳元标准。这个 澳元每年的经济负担估计为2000亿美元，澳元是可预防死亡的主要原因 在美国。持续的酒精滥用和依赖很难治疗，部分原因是酒精会增加 身体应激系统的反应性。压力系统的影响促进了“成瘾的黑暗面”， 而压力是引发复发的主要因素。因此，可以减轻压力的药物疗法--以及 依赖相关饮酒可以减少大量饮酒和压力引发的复发 患有澳元缺乏症的个人。我们最近发现，全身注射一种表观遗传酶 在一个临床前模型中，抑制剂减少了压力和依赖增强的酒精饮酒。我们已经提交了 为专利保护这一全新的MOA治疗AUD，提供了一条商业化的前进道路。在这 我们将评估我们的先导化合物的口服生物利用度，以检查是否 AUD治疗首选口服给药方法是可行的。我们还将检查最大耐受量 (MTD)和行为毒性措施。然后，我们将确定最佳的剂量条件，并寻求 建立强有力的原则证据数据，证明这些化合物可以减少依赖和压力相关的酒精 在多个临床前模型和多个品系的雄性和雌性小鼠中饮酒。在结束时 在这些目标中，我们预计将有足够的临床前信息用于后续的第二阶段STTR研究 瞄准未来的研究新药(IND)申请。

Project Summary The overall goal of this proposal is to characterize a lead compound with a novel mode of action (MOA) that reduces both stress- and dependence-related alcohol drinking in a preclinical model of Alcohol Use Disorder (AUD). AUD is a major problem in the U.S. as approximately 13.9% of adults meet AUD criteria per year. The annual economic burden of AUD is estimated at >$200 billion and AUD is a leading cause of preventable deaths in the USA. Persistent alcohol abuse and dependence is difficult to treat in part because alcohol increases the reactivity of the body’s stress systems. The influence of stress systems facilitates the “the dark side of addiction”, and stress is a primary factor that triggers relapse. Therefore, pharmacotherapies that can reduce stress- and dependence-associated alcohol drinking could reduce both heavy drinking and stress-triggered relapse in individuals suffering from AUD. We recently discovered that systemic administration of an epigenetic enzyme inhibitor reduced both stress- and dependence-potentiated alcohol drinking in a preclinical model. We have filed for patent protection of this entirely novel MOA to treat AUD, which provides a commercial path forward. In this Phase I STTR application, we will evaluate oral bioavailability of our lead compound to examine whether the preferred oral method of delivery is feasible for AUD treatment. We will also examine maximum tolerated dose (MTD) and behavioral toxicity measures. We will then determine optimal dosing conditions, and we seek to establish strong proof-of-principle data that these compounds reduce dependence- and stress-related alcohol drinking in multiple preclinical models and multiple mouse strains in both male and female mice. At the conclusion of these aims, we expect to have sufficient pre-clinical information for subsequent Phase II STTR studies targeting a future Investigational New Drug (IND) application.