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：
10659119
负责人：
Richard Joseph Johnson
金额：
$ 115.2万
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/10659119
关键词：
Adult Affect Alcohol consumption Alcohol dependence Alcoholism Alcohols Ames Assay Animals Applications Grants Automobile Driving Binding 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 Good Manufacturing Process 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 Phase Phase I 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 Signal Pathway Specificity Structure Sucrose 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 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 interest manufacturing organization medication safety meetings neurotransmission novel novel drug class novel therapeutics partial response pharmacologic phase 1 study phase I trial polyol pre-Investigational New Drug meeting 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.

酗酒和与酒精相关的疾病是全球范围内的一项重大健康挑战，在美国每年导致超过 88,000 人死亡，每年造成的公共卫生费用接近 2500 亿美元。目前的治疗方法包括咨询和支持小组以及降低饮酒欲望的药物。饮酒（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良反应的治疗（双硫仑），不幸的是，这些治疗提供了可变的和/或部分的反应；因此，我们需要长期关注的新疗法。驱动与糖相关的肝病的机制表明，这些机制也会影响对糖的渴望，这一新发现是这些相同的机制会影响对酒精的偏好。造成这些影响的机制涉及一种酶，即果糖激酶。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。根据这一发现，缺乏 KHK 的小鼠对酒精的偏好可以被显着阻断。抑制 KHK 的一个优点是抑制该靶标是安全的（缺乏果糖激酶的人类可以正常生活）并且涉及非生命途径（果糖代谢）。与其他干扰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），它们具有选择性，体内有活性，口服。生物利用度高，具有合理的药代动力学（PK）特征，我们组建了专家团队，拥有物质成分和使用方法的知识产权保护，并拥有强大的商业化计划。我们的首要目标是优化我们的先导化合物。通过：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、肝脏输送和代谢；3) 通过运行检测确保安全性；例如 CYP450 抑制谱、hERG 结合、蛋白激酶选择性筛选、Ames 试验以及体内安全毒性和致瘤性研究；以及 4) 完成临床前研究，重点关注使用药物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 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 概况。 FDA 在资助提案期结束前获得 IND 批准，完成这些研究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。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of thrifty genes in the origin of alcoholism: A narrative review and hypothesis.

节俭基因在酗酒起源中的作用：叙述回顾和假设。

DOI：
10.1111/acer.14655
发表时间：
2021-08
期刊：
Alcoholism, clinical and experimental research
影响因子：
0
作者：
Carn D;Lanaspa MA;Benner SA;Andrews P;Dudley R;Andres-Hernando A;Tolan DR;Johnson RJ
通讯作者：
Johnson RJ

The fructose survival hypothesis for obesity.

肥胖的果糖生存假说。

DOI：
发表时间：
2023-09-11
期刊：
影响因子：
0
作者：
Johnson, Richard J;Lanaspa, Miguel A;Sanchez;Tolan, Dean;Nakagawa, Takahiko;Ishimoto, Takuji;Andres;Rodriguez;Stenvinkel, Peter
通讯作者：
Stenvinkel, Peter