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

描述(由申请人提供)：非酒精性脂肪性肝炎(NASH)目前还没有特殊的治疗方法，它影响着2%-5%的美国人。该项目的长期目标是开发DB0930-007作为治疗NASH的创新药物。DB0930-007是一种新型的、高度特异的口服小分子激活剂5‘-AMP激活激酶(AMPK)。初步数据显示，给喂高脂饮食(HFD)的小鼠服用DB0930-007可以降低肝脏胆固醇、甘油三酯、游离脂肪酸、丙氨酸氨基转移酶(ALAT)、天冬氨酸转氨酶(ASAT)和β-谷氨酰转肽酶(GGT)，以控制饮食水平--重要的是没有肝脏毒性。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，这个第一阶段项目的具体目标是：1)开发一个改进的NASH模型，以确定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的抗炎效果。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一种潜在的治疗NASH的一流药物，为进一步发展到GLP/Tox阶段做好准备。NASH影响多达5%的美国人口，并将随着肥胖症的流行而增加患病率。它没有特别的治疗方法。AMPK激活剂代表了一种新颖、创新的方法，可能会彻底改变NASH的治疗方法。AMPK激活剂将被推向市场，用于治疗NASH，可能几乎没有副作用。

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.