LPA1 antagonist for alcoholic liver disease

LPA1拮抗剂治疗酒精性肝病

基本信息

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
项目类别：
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

项目摘要

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）：肝纤维化是一种疤痕形成形式，几乎所有患有慢性肝脏损伤的患者都会发现这种情况。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，是美国第七大死因，困扰着全世界数亿人。在西方国家，酒精摄入仍然是导致肝硬化的最重要原因。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）肝硬化。尽管已经在酒精性肝病患者中尝试了几种药物疗法，但迄今为止还没有一种疗法酒精性肝损伤的病程已显示出持续改善，但有效治疗的医疗需求仍然未得到满足。在我们的初步数据中，我们表明溶血磷脂酸受体 LPA1 拮抗剂在小鼠肝纤维化模型中具有抗纤维化活性。 Angion 已鉴定出一系列有前景的强效选择性小分子 LPA1 拮抗剂。该系列化合物具有优异的口服生物利用度，并在肺纤维化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证明。