A drug developed by researchers at the National Institutes of Health (NIH) limits the progression of liver fibrosis in mice, according to a prepared statement.
The new compound is a chemically modified version of ibipinapant, a brain-penetrating cannabinoid type 1 (CB-1) receptor antagonist used in scientific research. Senior author George Kunos’ team modified its structure to reduce its ability to penetrate the brain, and to include a molecular group that directly inhibits iNOS, the enzyme responsible for generating nitrogen compounds that promote inflammation.
Dr. Kunos and his team developed a new medication that concurrently inhibits both CB-1 receptors and iNOS.
“Inducible nitric oxide synthase, or iNOS, is an enzyme that has been shown to play a fundamental role in liver fibrosis pathology and is a potential target for fibrosis therapy,” Dr Kunos said in the statement. “It is also an important factor in alcoholic liver disease, viral hepatitis, fatty liver disease, and other pathologies that promote liver fibrosis.”
Previous studies have also shown that endocannabinoids, natural messengers in the body that help regulate many biological functions, play a role in liver fibrosis and, current compounds that block CB-1 receptors in the liver are moderately effective against liver fibrosis in animal models of the disease. However, because such compounds penetrate the brain and also block CB-1 receptors in the brain, they have undesirable psychiatric effects.
In the study, Dr Kunos and his colleagues tested the compounds in two widely-used mouse models of liver fibrosis unrelated to obesity. They found that the new compound was more effective in limiting fibrosis than compounds targeting either CB-1 receptors or iNOS alone.
Dr Kunos notes that, in addition to the new compound’s decreased ability to cause psychiatric side effects, it has also passed preliminary screening tests for other possible side effects such as genotoxicity or interactions with other receptors or ion channels that could generate “off-target” effects. He adds, however, that the compound will require more extensive safety screening in animals before seeking FDA approval for studies of its therapeutic potential in humans.
NIH. New medication shows promise against liver fibrosis in animal studies. Press releases. 2016.