Fructokinase Inhibitors for the Treatment of Alcohol Use Disorder

酗酒和与酒精相关的疾病是世界范围内的一个重大健康挑战，导致美国每年有超过88,000人死亡，每年的公共卫生成本接近2500亿美元。目前的治疗方法包括咨询和支持小组，加上减少饮酒欲望的药物（如通过改变阿片类药物和谷氨酸途径）或使用在饮酒时引起不愉快反应的治疗方法（双硫仑）。不幸的是，这些治疗提供了可变和/或部分的反应；因此，需要新的治疗方法。我们长期以来对驱动糖相关肝脏疾病的机制的兴趣表明，这些机制也会影响对糖的渴望。最大的突破是新发现，这些相同的机制影响对酒精的偏好。产生这些效应的机制涉及一种酶，果糖激酶（也称为酮己糖激酶（KHK）），它是果糖代谢（糖或蔗糖的一种成分）中的第一种酶。在缺乏KHK的小鼠中，对酒精的偏好可以被基本上阻断。根据这一发现，科罗拉多研究合作伙伴有限责任公司（CRP）研制出了对抗酒精中毒的新型药物。抑制KHK的一个优点是，对该靶点的抑制是安全的（人类缺乏果糖激酶可以正常生活），并且涉及非重要途径（果糖代谢），这与其他具有多能功能的干扰神经信号通路或具有严重副作用的干预措施相反。一些有效的化合物（60-160 nM Ki值）已经开发出来，它们具有选择性，体内活性，口服生物利用度，并且具有合理的药代动力学（PK）谱。我们组建了一个专家团队，拥有物质组成和使用方法的知识产权保护，并有强有力的商业化计划。我们的第一个目标将优化我们的先导化合物：1)利用计算机建模和晶体学来微调效价和选择性，以指导结构/活性关系（SAR）；2)优化口服生物利用度、肝脏给药和代谢；3)通过cyp450抑制谱、hERG结合、蛋白激酶选择性筛选、Ames试验、体内安全毒性和致瘤性研究等试验确保安全性；4)完成小鼠和大鼠模型的体内预防和治疗酒精成瘾疗效的临床前研究。我们的第二个目标将包括1)ind启用研究，包括我们的先导化合物在两个物种（大鼠和狗）中的最终毒性和PK谱。我们的期望是与FDA举行会议，在拨款提案期结束前获得IND批准。这些研究的完成将产生一种安全有效的新型药物，用于治疗酒精中毒和酒精使用障碍的第一阶段试验。

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.