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Peripheral CB1 Receptor Antagonist for Therapeutic Use in Metabolic Syndrome

During the last few decades, there has been an epidemic increase worldwide in the prevalence of obesity and its metabolic complications, including insulin resistance or diabetes, fatty liver, and changes in blood lipid profile. These metabolic abnormalities, in turn, can lead to coronary disease, liver cirrhosis and certain forms of cancer. There is no currently 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 peripheral tissues. They interact with the same cell surface receptors that also can recognize the psychoactive ingredient in marijuana and produce similar effects, such as an increase in appetite and increased synthesis and decreased degradation of lipids. In recent clinical trials, compounds that block the type‐1 cannabinoid (CB1) receptor were found effective not only in reducing the weight of obese individual, but also in reversing their associated insulin resistance, abnormal blood lipid profile and accumulation of fat in the liver. Unfortunately, these compounds also frequently elicited depression and anxiety, 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 brain. We have, therefore, modified the chemical structure of currently available CB1 blocking drugs in a way that markedly reduced their ability to penetrate the brain, 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 were devoid of the behavioral effects that predict neuropsychiatric effects in humans. Here, we request support from the NCATS BrIDGs program for 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.

Key Investigators

National Institute on Alcohol Abuse and Alcoholism (NIH)
George Kunos, M.D., Ph.D.

Jenrin Discovery, Inc.
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.

Outcomes

Approved studies are ongoing.

Project Details

  • Formulation development
  • PK/ADME studies
  • IND-directed toxicology

Contact

Tony Jackson