LPA1 antagonist for alcoholic liver disease

LPA1拮抗剂治疗酒精性肝病

• 批准号: 8524065
• 负责人: Bert J. W. M. Oehlen
• 金额: $ 25.1万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524065
• 关键词: Ablation; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Animal Model; Animals; Biological Availability; CCL4 gene; Canis familiaris; Cause of Death; Chronic; Cicatrix; Cirrhosis; Collaborations; Country; Data; Dermal; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Ensure; Enzymes; Etiology; Evaluation; Fibrosis; Future; G-Protein-Coupled Receptors; Gene Expression; Genetic; Grant; Histamine Release; Histology; Hydroxyproline; Immunohistochemistry; Injury to Liver; Kidney; Laboratories; Lead; Ligation; Liver; Liver Cirrhosis; Liver Fibrosis; Lung; Lysophosphatidic Acid Receptors; Lysophospholipids; Medical; Modeling; Mus; Oral; Patients; Pharmaceutical Preparations; Pharmacology; Preparation; Property; Pulmonary Fibrosis; Rattus; Research; Rodent Model; Role; Safety; Series; Serum; Staging; Testing; Therapeutic; Time; Toxicology; United States; Work; bile duct; design; drug efficacy; effective therapy; efficacy testing; in vivo; liver function; lysophosphatidic acid; mouse model; pre-clinical; problem drinker; public health relevance; research study; small molecule; tool; vzg-1 Receptor

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.

描述（由申请人提供）：肝纤维化是一种瘢痕形成形式，几乎在所有慢性肝损伤患者中发现。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死亡原因，并困扰着全世界数亿人。酒精摄入仍然是西方国家肝硬化的最重要原因。酒精性肝病可以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）肝硬化。尽管已经在酒精性肝病患者中尝试了几种药物治疗，但迄今为止， 在酒精性肝损伤的过程中显示出持续的改善，并且对于有效的治疗仍然存在重大的未满足的医疗需求。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已经鉴定出一系列有前途的强效和选择性小分子LPA 1拮抗剂。来自该系列的化合物具有优异的口服生物利用度，并且已经在肺纤维化的小鼠模型中显示出体内功效。本提案旨在测试肝纤维化啮齿动物模型中的先导化合物，从而为此类药物作为肝纤维化抗纤维化治疗的潜在用途建立概念验证。