Peripheral CB1 Receptor Antagonist for Therapeutic Use in Metabolic Syndrome

National Center For Advancing Translational Sciences

Investigators

Abstract

Obesity and its metabolic complications, including diabetes, changes in blood lipid profile and fatty liver disease have reached epidemic proportions worldwide. Currently, there is no available medication that simultaneously targets all of the metabolic consequences of obesity, justifying the search for novel approaches. In recent clinical trials, researchers found that compounds that block the type1 cannabinoid (CB1) receptor were effective not only in reducing the weight of obese individuals, but also in reversing their associated insulin resistance, abnormal blood lipid profile and accumulation of fat in the liver. Unfortunately, these compounds also elicited depression and anxiety frequently, which makes them unsuitable for therapeutic use. Studies in animal models of obesity have indicated that the beneficial metabolic effects of CB1 receptor blocking drugs is mediated, at least in part, by blockade of CB1 receptors in peripheral tissues, including the liver, fat and skeletal muscle cells, whereas their neuropsychiatric side effects are due to blockage of CB1 receptors in the brain. The investigators have modified the chemical structure of currently available CB1 blocking drugs in a way that reduced their ability to penetrate the blood-brain barrier but did not affect their oral bioavailability, selectivity and high affinity for the CB1 receptor. The project team will carry out longterm toxicology studies and oral formulation of a novel, peripherally restricted CB1 blocking compound for the treatment of the metabolic complications of obesity, primarily fatty liver disease with or without insulin resistance. The lab has made progress towards the completion of the following studies: - Formulation development - Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies - Investigational New Drug (IND)-directed toxicology