Research Project
8524065
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.
