Fructokinase Inhibitors for the Treatment of Alcohol Use Disorder

用于治疗酒精使用障碍的果糖激酶抑制剂

基本信息

批准号：
10221502
负责人：
Richard Joseph Johnson
金额：
$ 123.33万
依托单位：
COLORADO RESEARCH PARTNERS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221502
关键词：
Adult Affect Alcohol consumption Alcohol dependence Alcoholism Alcohols Ames Assay Animals Applications Grants Automobile Driving Binding Proteins Bioavailable Biological Assay Biological Availability Blood Canis familiaris Cessation of life Chemicals Clinic Clinical Clinical Trials Colorado Computer Models Contracts Counseling Coupled Crystallography Disease Disulfiram Dose Drug Kinetics Economics Enzymes Excretory function Experimental Designs Formulation Fructokinases Fructose Generations Glutamates Goals Guidelines Half-Life Health Health Care Costs Heavy Drinking Hepatic Human Intellectual Property International Interruption Intervention Intestinal Absorption Investigational Drugs Investigational New Drug Application Ketohexokinase Kinetics Lead Legal patent Liver diseases Maximum Tolerated Dose Measures Metabolic syndrome Metabolism Methods Microsomes Modeling Modification Molecular Weight Monitor Mus New Drug Approvals Opioid Oral Pathway interactions Performance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phase II/III Clinical Trial Phase III Clinical Trials Phosphotransferases Placebos Positioning Attribute Prevention Process Protein Kinase Public Health Rattus Reaction Recording of previous events Research Research Contracts Role Running Safety Self Administration Short Interspersed Nucleotide Elements Signal Pathway Specificity Structure-Activity Relationship Sucrose Sugar Alcohols Support Groups Testing Therapeutic Toxic effect Tumorigenicity United States United States Food and Drug Administration X-Ray Crystallography absorption addiction alcohol abuse therapy alcohol use disorder base cohort combat commercialization conditioned place preference craving cytotoxicity design drinking drug metabolism drug production efficacy study expectation good laboratory practice improved in vivo in vivo evaluation inhibitor/antagonist interest medication safety meetings neurotransmission novel novel drug class novel therapeutics partial response phase 1 study phase I trial polyol pre-clinical preclinical development preclinical study preference prototype recruit response safety study side effect small molecule social sugar virtual volunteer

项目摘要

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.

酒精中毒和与酒精相关的疾病代表了全世界的一项重大健康挑战，在美国，每年的公共卫生成本将近2500亿美元，导致了超过88,000人死亡。当前的治疗方法包括咨询和支持小组，再加上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），或通过使用饮酒时引起不愉快反应的治疗方法（二硫酸氢酯）。不幸的是，这些治疗方法提供了可变和/或部分反应。因此，需要新的疗法。我们对驱动与糖相关肝病的机制的长期兴趣表明，这些机制也会影响糖的渴望。最大的突破是新发现，即这些相同的机制会影响对酒精的偏爱。负责这些作用的机制涉及一种酶，果糖酶（也称为酮己激酶（KHK）），该酶是果糖代谢（糖或蔗糖的成分）中的第一种酶。在缺乏KHK的小鼠中，对酒精的偏好可能会大大阻止。根据这一发现，科罗拉多州研究伙伴有限责任公司（CRP）产生了新的毒品类毒品类药物。抑制KHK的一个优势是，对该靶标的抑制是安全的（人类缺乏果糖酶正常生存），并且涉及一种非重要途径（果糖代谢），这与其他干预措施相反，这些干预措施中断具有多能功能或具有严重副作用的神经信号途径。已经开发了几种潜在的化合物（60-160 nm Ki值），它们具有选择性，活性在体内，口服生物利用度，并且具有合理的药代动力学（PK）剖面。我们组建了一个专家团队，拥有构成和使用方法的知识产权保护，并制定了强大的商业化计划。我们的第一个目标将通过以下方式优化我们的铅化合物：1）使用计算机建模和晶体学来指导结构/活动关系（SAR）进行微调效力和选择性； 2）优化口服生物利用度，肝脏递送和代谢； 3）通过运行测定法，例如CYP450抑制作用，HERG结合，蛋白激酶 - 选择性筛查，AMES测试以及体内安全性毒性和肿瘤性研究，以确保安全性； 4）临床前研究的完成，重点是使用鼠类和大鼠模型来预防和治疗酒精成瘾的体内效率。我们的第二个目标包括1）辅助研究，包括我们铅化合物的最终毒性和两种物种（大鼠和狗）的PK谱。我们的期望是与FDA开会，以在赠款提案期结束之前获得IND批准。这些研究的完成将导致一种安全有效的药物的新型类别，该药物定位为1阶段试验，以治疗酒精中毒和酒精疾病。