A novel, orally available small molecule AMPK activator as a treatment for non al

一种新型口服小分子 AMPK 激活剂，可用于治疗非

• 批准号: 8703875
• 负责人: John M Kyriakis
• 金额: $ 14.74万
• 依托单位: MERCURY THERAPEUTICS. INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703875
• 关键词: 5' -AMP-activated protein kinase; Adverse effects; Affect; Alanine Transaminase; American; Anti-Inflammatory Agents; Anti-inflammatory; Aspartate Transaminase; Attenuated; Biochemical; Biological Assay; Biological Models; Cells; Characteristics; Cholesterol; Cirrhosis; Data; Development; Diet; Disease; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Future; Gamma-glutamyl transferase; Goals; Hepatic; Hepatotoxicity; Inflammation; Inflammatory; Insulin Resistance; Intervention; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Marketing; Medical; Mercury; Metabolic; Modeling; Mus; Nonesterified Fatty Acids; Obesity; Outcome Study; Pathology; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; Prevalence; Prevention; Primary carcinoma of the liver cells; Procedures; Protein Kinase; Reducing diet; Risk Factors; Staging; Steatohepatitis; Streptozocin; Testing; Therapeutic; Toxic effect; Triglycerides; United States; Work; effective therapy; feeding; improved; in vivo; inflammatory marker; innovation; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; pandemic disease; pre-clinical; public health relevance; small molecule

DESCRIPTION (provided by applicant): No specific therapies exist for nonalcoholic steatohepatitis (NASH), which affects 2-5% of Americans. The long term goal of this project is to develop DB0930-007-a novel, highly specific, orally available small molecule activator of 5'-AMP-activated kinase (AMPK)-as an innovative treatment for NASH. Preliminary data indicate that administration of DB0930-007 to mice fed a high fat diet (HFD) reduces hepatic cholesterol, triglycerides, free fatty acids, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and ?-glutamyl transpeptidase (GGT) to control diet levels-importantly with no liver toxicity. The HFD model is, on its own, insufficient for the complete analysis of NASH. Notably, the ability of our compound to reduce NASH inflammation is unknown. Accordingly, the Specific Aims for this Phase I project are: 1) Exploit an improved NASH model to determine if DB0930-007 can reverse the metabolic and fibrotic pathologies of NASH. A streptozotocin/HFD procedure will be used 2) Determine the anti-inflammatory effects of DB0930-007. Biochemical, immunohistochemical and cell biological assays will be employed along with our NASH model. The expected outcome of these studies will be the identification of a potential first in class treatment for NASH, ready for further development to GLP/Tox stage. NASH affects up to 5% of the US population and will increase in prevalence with the obesity pandemic. It has no specific treatment. AMPK activators represent a novel, innovative approach that could revolutionize NASH treatment. AMPK activators would be marketed to treat NASH with potentially few side effects.

描述（由申请人提供）：非酒精性脂肪性肝炎 (NASH) 尚无特效疗法，该疾病影响 2-5% 的美国人。该项目的长期目标是开发 DB0930-007——一种新型、高度特异性、口服的 5'-AMP 激活激酶 (AMPK) 小分子激活剂——作为 NASH 的创新治疗方法。初步数据表明，给高脂饮食 (HFD) 喂养的小鼠施用 DB0930-007 可以降低肝脏胆固醇、甘油三酯、游离脂肪酸、丙氨酸转氨酶 (ALAT)、天冬氨酸转氨酶 (ASAT) 和 γ-谷氨酰转肽酶 (GGT)，从而控制饮食水平——重要的是没有肝脏毒性。 HFD 模型本身不足以完整分析 NASH。值得注意的是，我们的化合物减少 NASH 炎症的能力尚不清楚。因此，该第一阶段项目的具体目标是： 1) 利用改进的 NASH 模型来确定 DB0930-007 是否可以逆转 NASH 的代谢和纤维化病理。将使用链脲佐菌素/HFD 程序2) 确定DB0930-007 的抗炎作用。生物化学、免疫组织化学和细胞生物学检测将与我们的 NASH 模型一起使用。这些研究的预期结果将是确定 NASH 的潜在一流治疗方法，为进一步开发至 GLP/Tox 阶段做好准备。 NASH 影响着高达 5% 的美国人口，并且随着肥胖的流行，患病率将会增加。它没有具体的治疗方法。 AMPK 激活剂代表了一种新颖的创新方法，可以彻底改变 NASH 治疗。 AMPK 激活剂将用于治疗 NASH，且副作用可能很少。