Fructokinase Inhibitors for the Treatment of Alcohol Use Disorder

酒精中毒和与酒精相关的疾病是世界范围内的一个重大健康挑战，在美国每年导致超过8.8万人死亡，每年公共卫生成本近2500亿美元。目前的治疗方法包括咨询和支持小组，以及减少饮酒欲望的药物(例如通过改变阿片类药物和谷氨酸途径)，或者通过使用在饮酒时引起不愉快反应的治疗(双硫兰)。不幸的是，这些治疗提供了不同的和/或部分反应；因此，需要新的治疗方法。我们长期以来对糖相关肝病的驱动机制的兴趣揭示了这些机制也影响着对糖的渴求。最大的突破是一项新的发现，即这些相同的机制影响着人们对酒精的偏好。负责这些作用的机制涉及一种酶，果糖激酶(也称为酮己糖激酶(KHK))，它是果糖代谢(糖的一种成分，或蔗糖的一种成分)的第一种酶。在缺乏KHK的小鼠中，酒精的偏好可以被很大程度上阻止。根据这一发现，科罗拉多州研究伙伴有限责任公司(CRP)创造了新的一流药物来对抗酒精中毒。抑制KHK的一个优点是，抑制这一靶点是安全的(缺乏果糖激酶的人正常生活)，并涉及非生命途径(果糖代谢)，这与其他干扰具有多功能的神经信号通路或具有严重副作用的干预相反。一些有效的化合物(60-160 nM KI值)已经被开发出来，它们具有选择性、体内活性、口服生物利用度和合理的药代动力学(PK)曲线。我们组建了一支专家团队，既有物质组成又有使用方法的知识产权保护，并有很强的商业化计划。我们的第一个目标将通过以下方面优化我们的先导化合物：1)使用计算机建模和结晶学来指导结构/活性关系(SAR)的微调效力和选择性；2)优化口服生物利用度、肝脏给药和代谢；3)通过运行CYP450抑制谱、HERG结合、蛋白激酶选择性筛选、Ames试验和体内安全毒性和致瘤性研究等方法确保安全性；以及4)完成临床前研究，重点关注使用小鼠和大鼠模型预防和治疗酒精成瘾的体内疗效。我们的第二个目标将包括1)支持IND的研究，包括我们的先导化合物在两个物种(老鼠和狗)中的最终毒性和PK谱。我们希望在拨款建议期结束前与FDA举行一次会议，以获得IND的批准。这些研究的完成将导致一种安全有效的新型药物，为治疗酒精中毒和酒精使用障碍的第一阶段试验奠定了基础。

Alcoholism and alcohol-associated diseases represent a major health challenge worldwide, leading to over 88,000 annual deaths in the USA at an annual public-health cost of nearly 250 billion dollars. Current treatments include counseling and support groups coupled with medications that reduce the desire to drink (such as by altering opioid and glutamate pathways) or by use of treatments that cause unpleasant reactions while drinking (disulfiram). Unfortunately, these treatments provide variable and/or partial responses; so, new therapies are needed. Our longstanding interest in mechanisms driving sugar-associated liver disease have revealed that these mechanisms affect sugar craving as well. The big breakthrough was the novel discovery that these same mechanisms affect the preference for alcohol. The mechanism responsible for these effects involves an enzyme, fructokinase (also known as ketohexokinase (KHK)), which is the first enzyme in fructose metabolism (a component of sugar, or sucrose). The preference for alcohol can be substantially blocked in mice lacking KHK. Pursuant to this discovery, new first in class of drugs to combat alcoholism have been generated by Colorado Research Partners, LLC (CRP). An advantage to inhibition of KHK is that inhibition of this target is safe (humans lacking fructokinase live normally) and involves a non-vital pathway (fructose metabolism), which is in opposition to other interventions that interrupt neural signal pathways with pluripotent functions or have severe side effects. Several potent compounds (60–160 nM Ki values) have been developed, which are selective, active in vivo, orally bioavailable, and have reasonable pharmacokinetic (PK) profiles. We have assembled an expert team, have both composition-of-matter and methods-of-use intellectual property protection, and have a strong commercialization plan. Our first aim will optimize our lead compound by: 1) Fine tuning the potency and selectivity using computer modeling and crystallography to guide the structure/activity relationship (SAR); 2) Optimizing oral bioavailability, hepatic delivery and metabolism; 3) Assuring safety by running assays such as CYP450-inhibition profile, hERG binding, protein kinase-selectivity screen, Ames test, and in vivo safety-toxicity and tumorigenicity studies; and 4) Completion of preclinical studies focusing on in vivo efficacy for both prevention and treatment of alcohol addiction using murine and rat models. Our second aim will include 1) IND-enabling studies including final toxicity and PK profiles of our lead compound in two species (rat and dog). Our expectation is to have a meeting with the FDA to obtain IND approval by the end of the grant proposal period. Completion of these studies will result in a safe and effective drug of a novel class positioned for Phase 1 trials to treat alcoholism and alcohol-use disorders.