Novel insulin-sensitizing NASH/diabetes drugs.

肥胖与许多慢性和进行性疾病和肥胖的风险增加有关- 相关的代谢疾病构成了重大的公共卫生负担。的可能性增加 发展胰岛素抵抗和糖尿病可能是最常见的肥胖风险。在 此外，肥胖症还与肝实质中脂质的积累（肝脂肪变性或肝硬化）有关。 非酒精性脂肪肝（NAFLD））。术语NAFLD包括肝脂肪变性（脂肪变性）和肝硬化。 中性脂质在肝细胞胞浆内的积累）和更严重的非酒精性 脂肪性肝炎（NASH）（与脂肪性病变相关的肝脏炎症和纤维化）。显著 部分NAFLD和NASH患者将进展为肝硬化和肝功能衰竭， 发展成肝细胞癌NASH目前是一种没有批准治疗的疾病， 这是一个严重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的发展密切相关，因此靶向这些贡献途径的药物是领先的。 治疗疾病的候选人。此应用程序旨在测试新的胰岛素增敏剂的功效 通过新的机制发挥作用以改善胰岛素作用同时减少副作用的药物。我们将研究A 新的原型化合物（MSDC-5514）及其备用化合物（MSDC-5445）治疗胰岛素的功效 耐药性和NASH。在第一阶段，我们将确定这些化合物是否改善胰岛素敏感性 并验证磷脂酶D1（PLD 1）信号转导是其分子靶点的假设。在第二阶段，我们将 检查MSDC-5514和MSDC-5445在NASH小鼠模型中的肝脏作用，并验证PLD 1 在这个模型中，在这些研究中获得的结果将定义机制，并提供证据- 支持未来临床试验的概念证据，以测试这些药物在糖尿病患者中的疗效 以及其他与肥胖相关的心脏代谢疾病，这些疾病有可能使数百万美国人受益。

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.