Treatment for alcoholic liver disease

描述(由申请人提供)：肝纤维化是一种疤痕形成形式，几乎在所有慢性肝损伤患者中都能发现。随着时间的推移，它经常进展为肝硬变，这是一种终末期致命疾病，是美国第七大主要死亡原因，困扰着全球数亿人。在西方国家，酒精摄入仍然是导致肝硬变的最重要原因。酒精性肝病可分为不同的发展阶段：(1)轻度酒精性肝损伤，(2)脂肪变性，(3)酒精性肝炎，(4)酒精性肝纤维化和(5)肝硬变。尽管已经尝试了几种药物疗法用于酒精性肝病患者，但到目前为止，没有一种疗法在酒精性肝损伤的过程中显示出持续的改善，对有效疗法的主要医学需求仍然没有得到满足。在我们的初步数据中，我们显示内源性ATRA水平的调节剂在小鼠中具有抗纤维化活性。我们已经确定了一系列具有良好的体内外药理作用的新型全反式维甲酸调节剂，并在体内证明了其抗纤维化活性。我们建议将这一系列的先导化合物作为酒精性肝病的潜在治疗药物提名。

DESCRIPTION (provided by applicant): Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. Alcohol intake remains the most important cause of liver cirrhosis in Western countries. Alcoholic liver disease can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. In our preliminary data, we show that modulators of endogenous ATRA levels have anti-fibrotic activity in mice. We have identified a novel series of ATRA modulators with excellent in vitro and in vivo pharmacological properties and demonstrate its anti-fibrotic activity in vivo. We propose to pursue the lead compound from this series towards an IND nomination as a potential therapeutic for alcoholic liver disease.