Scientific Merit and Feasibility of Fructokinase Inhibition for Obesity

果糖激酶抑制治疗肥胖的科学价值和可行性

• 批准号: 9464351
• 负责人: Richard Joseph Johnson
• 金额: $ 28.94万
• 依托单位: COLORADO RESEARCH PARTNERS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9464351
• 关键词: Acute; Adenosine Kinase; Adverse effects; Aging; Aldolase B; Ames Assay; Animal Disease Models; Animal Model; Animals; Area; Automobile Driving; Binding; Binding Proteins; Biological; Biological Assay; Biological Availability; Blood Pressure; Body Weight; Botanicals; Carbohydrates; Carbon; Chemicals; Chronic Kidney Failure; Computer Simulation; Consumption; Crystallization; Diabetes Mellitus; Diet; Drug Design; Drug Kinetics; Drug or chemical Tissue Distribution; Eating; Enzymes; Epidemic; Ethers; Experimental Models; Fatty Liver; Food; Fructokinases; Fructose; Genes; Goals; Hereditary fructose intolerance syndrome; Human; In Vitro; Indazoles; Insulin Resistance; Intake; Ketohexokinase; Kidney Diseases; Knock-out; Laboratory Animals; Lead; Legal patent; Leptin resistance; Liver; Longevity; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Modification; Molecular Weight; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutraceutical; Nutrient; Obesity; Oral; Oral Administration; Orphan Drugs; Pathology; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Plasma Proteins; Play; Positioning Attribute; Production; Property; Purine Nucleotides; Rare Diseases; Reporting; Ribose; Role; Series; Small Business Technology Transfer Research; Solubility; Source; Specificity; Structure; Structure-Activity Relationship; Sucrose; Suggestion; Surface; Testing; Therapeutic Agents; Toxic effect; Toxicity Tests; Toxicology; Uric Acid; Work; X-Ray Crystallography; base; chemical synthesis; commercialization; craving; design; efficacy study; experimental study; fatty acid oxidation; fructose-1-phosphate; high salt diet; high throughput screening; in vivo; inhibitor/antagonist; inorganic phosphate; interest; non-alcoholic fatty liver; novel; phase 1 study; preclinical development; prevent; programs; research clinical testing; sugar; western diet

Our goal is to develop a first -in-class therapeutic agent that directly blocks the metabolism of fructose, a key component in sugar. Intake of sugar (sucrose) and high fructose corn syrup (HFCS) induces metabolic syndrome and diabetes in laboratory animals and are strongly associated with obesity and diabetes in humans. Both sucrose and HFCS contain fructose, which stimulates food intake by inducing leptin resistance while lowering metabolism, including blocking fatty-acid oxidation. We found that these effects of fructose were mediated by the unique ability of fructose to decrease intracellular-ATP levels during its metabolism, which is due to the rapid consumption of ATP by the enzyme fructokinase C (KHK-C) in the liver. Mice lacking KHK-C are protected from sugar-induced obesity, fatty liver, and metabolic syndrome. While sugar and HFCS are major sources of dietary fructose, we found that fructose can be endogenously produced by high glycemic or high salt diets and that blocking fructokinase protects animals from obesity and insulin resistance from this source of fructose. Furthermore, mice lacking fructokinase are also protected from the orphan disease, hereditary fructose intolerance (HFI). Blocking KHK-C is safe, as humans lacking have a normal life span and mice lacking KHK-C are even protected from aging-associated kidney disease. In Phase I of our STTR, our goal was to develop two novel lead compounds with IC50 values in the submicromolar range that were effective at blocking KHK-C both in vitro and in vivo and with specificity for KHK compared to other sugar kinases. While much of our initial effort was aimed at developing derivatives of a nutraceutical (osthol) as novel chemical entities, we were unable to break the submicromolar-IC50 target. However, more recently a series of novel indazole compounds has been identified, which have high potency and selectivity, and have robust in vivo activity after oral administration. In this Phase II proposal, we plan to optimize our lead inhibitors using structure-based drug design (SBDD). Aim 1 is to optimize our lead inhibitors with increased potency (IC50 <40 nM) and selectivity guided by SBDD. In Aim 2, the most promising lead compounds will be evaluated in in vitro ADME assays (e.g. solubility, permeability, microsomal stability) and in vitro toxicity (e.g. CYP450 inhibition, Ames test and hERG inhibition. Inhibitors of high interest will undergo in vivo pharmacokinetic (PK) profiling and exploratory toxicity testing. Aim 3 is to test these lead compounds in our unique animal disease models for long-term efficacy at blocking fructose-induced fatty liver, nonalcoholic fatty liver disease, and metabolic syndrome, as well the protection of mice with HFI (due to knockout of the aldolase B gene) towards fructose. Inhibitors with robust efficacy will also be evaluated in exploratory toxicology studies. Completion of these studies should result in an optimal preclinical development candidate for a first-in- class drug for those suffering from HFI and metabolic syndrome.

我们的目标是开发一种一流的治疗剂，直接阻断果糖的代谢，这是一个关键 糖的成分。摄入糖（蔗糖）和高果糖玉米糖浆（HFCS）可诱发代谢综合征 和糖尿病，并与人类的肥胖和糖尿病密切相关。两 蔗糖和HFCS含有果糖，果糖通过诱导瘦素抗性刺激食物摄入，同时降低 代谢，包括阻断脂肪酸氧化。我们发现果糖的这些作用是由 果糖在其代谢过程中降低细胞内ATP水平的独特能力，这是由于快速的 肝脏中果糖激酶C（KHK-C）消耗ATP。缺乏KHK-C的小鼠受到保护， 糖引起的肥胖、脂肪肝和代谢综合征。虽然糖和HFCS是膳食的主要来源， 果糖，我们发现果糖可以通过高血糖或高盐饮食内源性产生， 阻断果糖激酶可以保护动物免于肥胖和胰岛素抵抗。 此外，缺乏果糖激酶的小鼠也不会患上孤儿病，遗传性果糖 不容忍（HFI）。阻断KHK-C是安全的，因为缺乏KHK-C的人有正常的寿命，而缺乏KHK-C的小鼠 甚至可以预防与衰老相关的肾脏疾病。在STTR的第一阶段，我们的目标是开发两个 IC 50值在亚微摩尔范围内的新型先导化合物有效阻断KHK-C， 并且与其它糖激酶相比对KHK具有特异性。虽然我们最初的努力 的目的是开发衍生物的营养（ossimetry）作为新的化学实体，我们无法 突破亚微摩尔IC 50目标。然而，最近一系列新的吲唑化合物已经被发现。 这些化合物具有高效力和选择性，并且在口服给药后具有稳健的体内活性。在 在这个II期计划中，我们计划使用基于结构的药物设计（SBDD）来优化我们的先导抑制剂。目的 1是优化我们的先导抑制剂，提高效力（IC 50 <40 nM）和SBDD指导的选择性。在Aim中 2，最有前途的先导化合物将在体外ADME测定中进行评价（例如溶解性，渗透性， 微粒体稳定性）和体外毒性（例如CYP 450抑制、艾姆斯试验和hERG抑制。的抑制剂 高兴趣者将经历体内药代动力学（PK）分析和探索性毒性测试。目标3：测试 这些先导化合物在我们独特的动物疾病模型中长期有效地阻断果糖诱导的 脂肪肝、非酒精性脂肪肝和代谢综合征，以及HFI（由于 敲除醛缩酶B基因）。还将评估具有稳健疗效的抑制剂， 探索性毒理学研究。这些研究的完成应导致最佳的临床前开发 对于那些患有HFI和代谢综合征的人来说，这是一流的药物候选人。