Novel insulin-sensitizing NASH/diabetes drugs.

新型胰岛素增敏 NASH/糖尿病药物。

• 批准号: 10096091
• 负责人: Brian N Finck
• 金额: $ 49.75万
• 依托单位: BIOIO, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10096091
• 关键词: American; Antidiabetic Drugs; B-Lymphocytes; Bioavailable; Biochemical; Biological Assay; Blood Glucose; Blood Preservation; CRISPR interference; Chronic Disease; Cirrhosis; Clinical Trials; Collaborations; Cytosol; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Drug usage; Excretory function; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Future; Glucose; Glucose Clamp; Hepatic; Hepatocyte; Homeostasis; In Vitro; Inflammation; Insulin; Insulin Resistance; Lesion; Link; Lipids; Liver Failure; Liver diseases; Liver parenchyma; Mediating; Medical; Metabolic; Metabolic Diseases; Metformin; Modeling; Molecular; Molecular Analysis; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phenotype; Phospholipase D; Phospholipases A; Primary carcinoma of the liver cells; Progressive Disease; Public Health; Refractory; Risk; Rodent; Signal Transduction; Sulfonylurea Compounds; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Tissues; Toxicology; Validation; Work; base; cardiometabolism; comorbidity; design; drug efficacy; efficacy testing; glucose production; improved; in vivo; inhibitor/antagonist; insulin secretion; insulin sensitivity; insulin sensitizing drugs; intrahepatic; lead candidate; liver injury; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; phospholipase D1; prototype; screening; side effect; stellate cell; urinary

Obesity is associated with an increased risk of a number of chronic and progressive diseases and obesity- related metabolic diseases constitute a significant public health burden. The increased likelihood of developing insulin resistance and diabetes is probably the most commonly recognized risk of being obese. In addition, obesity is also associated with accumulation of lipid in the liver parenchyma (hepatic steatosis or nonalcoholic fatty liver disease (NAFLD)). The term, NAFLD, encompasses both hepatic steatosis (the accumulation of neutral lipid within the cytosol of hepatocytes) and the more severe nonalcoholic steatohepatitis (NASH) (hepatic inflammation and fibrosis associated with steatotic lesions). A significant proportion of NAFLD and NASH patients will progress to cirrhosis and liver failure and are at increased risk for developing hepatocellular carcinoma. NASH is currently a disease without an approved treatment and constitutes a significant unmet medical need. Importantly, inflammation, insulin resistance, and diabetes are tightly linked to development of NASH and thus drugs that target these contributing pathways are lead candidates for treating the disease. This application is designed to test the efficacy of new insulin-sensitizing agents that act via a novel mechanism to improve insulin action while reducing side effects. We will study a novel prototype compound (MSDC-5514) and its backup (MSDC-5445) for efficacy at treating insulin resistance and NASH. In Phase I, we will determine whether these compounds improve insulin sensitivity and test the hypothesis that phospholipase D 1 (PLD1) signaling is their molecular target. In Phase II, we will examine the hepatic effects of MSDC-5514 and MSDC-5445 in a mouse model of NASH and validate PLD1 genetically in this model. Findings obtained in these studies will define mechanisms and provide proof-of- concept evidence supporting future clinical trials to test the efficacy of these drugs in patients with diabetes and other obesity-related cardiometabolic diseases that have the potential to benefit millions of Americans.

肥胖与多种慢性和进行性疾病的风险增加有关，肥胖 相关的代谢疾病构成了巨大的公共卫生负担。增加的可能性 发展胰岛素抵抗和糖尿病可能是肥胖的最常见的风险。在 此外，肥胖还与肝实质（肝脂肪变性或 非酒精性脂肪肝病（NAFLD））。 nafld术语涵盖了肝脂肪变性（ 中性脂质在肝细胞的胞质溶胶中的积累）和更严重的非酒精性 脂肪性肝炎（NASH）（肝炎和纤维化与脂肪变病变相关）。重要的 NAFLD和NASH患者的比例将发展为肝硬化和肝脏衰竭，并且风险增加 用于发展肝细胞癌。纳什目前是一种没有批准治疗的疾病 构成了巨大的未满足的医疗需求。重要的是，炎症，胰岛素抵抗和糖尿病是 与NASH的发展紧密相关，因此针对这些贡献途径的药​​物是铅 治疗疾病的候选人。该应用程序旨在测试新胰岛素敏感性的功效 通过新型机制起作用的代理，以改善胰岛素作用，同时减少副作用。我们将研究 新型原型化合物（MSDC-5514）及其备份（MSDC-5445）用于治疗胰岛素 阻力和纳什。在第一阶段，我们将确定这些化合物是否提高胰岛素敏感性 并检验以下假设：磷脂酶D 1（PLD1）信号传导是它们的分子靶标。在第二阶段，我们将 检查MSDC-5514和MSDC-5445在NASH和验证PLD1中的肝效应 在此模型中遗传。在这些研究中获得的发现将定义机制，并提供证明 支持未来临床试验以测试这些药物在糖尿病患者中的功效的概念证据 以及其他与肥胖相关的心脏代谢疾病，有可能使数百万美国人受益。