Fructokinase Inhibitors for the Treatment of Alcohol Use Disorder

酒精中毒和酒精相关疾病代表了世界范围内的主要健康挑战，在美国每年导致超过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团体，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）或使用在饮酒时引起不愉快反应的治疗（双硫仑）。不幸的是，这些治疗提供可变和/或部分响应;因此，需要新的疗法。我们对糖相关肝病驱动机制的长期兴趣表明，这些机制也会影响对糖的渴望。最大的突破是新发现，这些机制影响了对酒精的偏好。负责这些作用的机制涉及一种酶，果糖激酶（也称为己酮糖激酶（KHK）），它是果糖代谢（糖或蔗糖的组分）中的第一种酶。在缺乏KHK的小鼠中，对酒精的偏好可以基本上被阻断。根据这一发现，科罗拉多研究伙伴有限责任公司（CRP）已经产生了新的第一类药物，以打击酗酒。抑制KHK的一个优点是抑制该靶点是安全的（缺乏果糖激酶的人可以正常生活），并且涉及非生命途径（果糖代谢），这与其他干扰具有多能功能的神经信号通路或具有严重副作用的干预措施相反。已经开发了几种有效的化合物（60-160 nM Ki值），其具有选择性、体内活性、口服生物可利用性，并且具有合理的药代动力学（PK）特征。我们已经组建了一个专家团队，拥有物质成分和使用方法的知识产权保护，并有强大的商业化计划。我们的第一个目标将通过以下方式优化我们的先导化合物：1）使用计算机建模和晶体学来微调效力和选择性以指导结构/活性关系（SAR）; 2）优化口服生物利用度、肝脏递送和代谢; 3）通过进行测定如CYP 450抑制曲线、hERG结合、蛋白激酶选择性筛选、艾姆斯试验来确保安全性，以及体内安全性-毒性和致瘤性研究;以及4）完成临床前研究，重点是使用小鼠和大鼠模型预防和治疗酒精成瘾的体内功效。我们的第二个目标将包括1）IND使能研究，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特征。我们的期望是与FDA举行会议，以在资助提案期结束前获得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1期试验。

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.