LPA1 antagonist 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来治疗酒精性肝病，但到目前为止还没有一种疗法。 在酒精性肝损伤的过程中显示出持续的改善，有效治疗的主要医学需求仍然没有得到满足。在我们的初步数据中，我们表明溶血磷脂酸受体LPA1的拮抗剂在小鼠肝纤维化模型中具有抗纤维化活性。Angion已经发现了一系列有效的、选择性的小分子LPA1拮抗剂。该系列化合物具有极好的口服生物利用度，并在小鼠肺纤维化模型中显示出体内疗效。本提案的目的是在肝纤维化的啮齿动物模型中测试先导化合物，从而为此类药物作为抗肝纤维化治疗的潜在用途奠定概念证据。

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 an antagonist of the Lysophosphatidic Acid Receptor LPA1 has anti-fibrotic activity in a mouse model of liver fibrosis. Angion has identified a promising series of potent and selective small molecule LPA1 antagonist. Compounds from this series have excellent oral bioavailability and have shown in vivo efficacy in a mouse model of pulmonary fibrosis. The present proposal is designed to test lead compounds in rodent models of liver fibrosis and thus establish proof of concept for the potential use of such agents as an antifibrotic therapy in liver fibrosis.