Peripheral CB1 Receptor Antagonist for Therapeutic Use in Metabolic Syndrome

Obesity has dramatically increased in the United States in recent decades; more than one-third of adults are obese. Obesity can lead to a variety of complications, including insulin resistance, buildup of fat in the liver and high cholesterol. Over time, these conditions can lead to diabetes, heart and liver disease, and cancer. No drugs exist that treat all of the complications of obesity. Recently, scientists tested a drug that blocks the activity of a type of chemical called endocannabinoids. These chemicals act as signaling molecules at the same receptors that recognize the active ingredient in marijuana, and they produce similar effects, including increased appetite and boosts in mood. The researchers found that the drug caused weight loss and reduced levels of insulin resistance, cholesterol and fat in the liver. However, the drug also caused depression and anxiety, making it not suitable for use as a therapy. The investigators have developed a drug that similarly blocks the effects of endocannabinoids but that cannot enter pass through the blood-brain barrier to produce unwanted psychological effects. The team will continue to prepare the drug for testing in human clinical trials of obesity and fatty liver disease.

Scientific Synopsis

During the last few decades, there has been an epidemic increase in the worldwide prevalence of obesity and its metabolic complications, including insulin resistance, diabetes, fatty liver and changes in blood lipid profile. These metabolic abnormalities, in turn, can lead to coronary heart disease, liver cirrhosis and certain forms of cancer. Currently, there is no available medication that simultaneously targets all of the metabolic consequences of obesity, justifying the search for novel approaches. Endocannabinoids are lipid‐like signaling molecules present in the brain as well as in peripheral tissues. They interact with the same cell surface receptors that also recognize the psychoactive ingredient in marijuana, and they produce similar effects, such as an increase in appetite and increased synthesis and decreased degradation of lipids. 

In recent clinical trials, researchers found that compounds that block the type‐1 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. When tested in mouse models of obesity, such compounds were equally as effective as their brain‐penetrant parent compounds in improving obesity‐related metabolic abnormalities, but they were devoid of the behavioral effects that predict neuropsychiatric effects in humans. The project team will carry out long‐term 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.

Lead Collaborators

National Institute on Alcohol Abuse and Alcoholism, NIH

 George Kunos, M.D., Ph.D.

Jenrin Discovery, Inc., West Chester, Pennsylvania

John McElroy, Ph.D.

Robert Chorvat, Ph.D.

Public Health Impact

Obesity and its metabolic complications, including diabetes, changes in blood lipid profile and fatty liver disease have reached epidemic proportions worldwide. This class of compounds has the promise to be a novel and effective treatment of the metabolic abnormalities caused by obesity, and we propose to develop one such compound for testing in humans.


 BrIDGs program scientists completed formulation development, manufacture of Good Manufacturing Practice (GMP) drug product, and pharmacokinetic and IND-directed toxicology studies As a result of BrIDGs support, the collaborators were able to file an IND application, which was cleared by the Food and Drug Administration in December 2017. The team is continuing to evaluate a high-dose formulation of the drug.