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）没有特定的治疗方法，影响2-5%的美国人。该项目的长期目标是开发db0930 -007-一种新型的，高度特异性的，口服可获得的5'- amp活化激酶（AMPK）的小分子活化剂，作为NASH的创新治疗方法。初步数据表明，高脂饲料（HFD）小鼠给予DB0930-007可降低肝脏胆固醇、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？-谷氨酰转肽酶（GGT）来控制饮食水平，重要的是没有肝毒性。HFD模型本身不足以对NASH进行完整的分析。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，本一期项目的具体目标是：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。2)确定DB0930-007的抗炎作用。生化，免疫组织化学和细胞生物学分析将与我们的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，为进一步发展到GLP/Tox阶段做好准备。NASH影响高达5%的美国人口，并将随着肥胖的流行而增加。它没有特殊的治疗方法。AMPK激活剂代表了一种新颖的、创新的方法，可以彻底改变NASH的治疗。AMPK激活剂将用于治疗NASH，副作用可能很少。