Liver fibrosis is a progressive scarring of the liver brought on by chronic alcoholism, viral hepatitis, obesity or diabetes. The condition could lead to cirrhosis and cancer of the liver. Despite its prevalence, there is no mainstay treatment to prevent scarring.
Now researchers at the National Institutes of Health (NIH) have reported developing a drug that limits liver fibrosis in mice. The findings have been published online in the journal JCI Insight.
The drug was synthesized using the chemical structure of ibipinapant--a brain-penetrating CB-1 receptor antagonist--as the backbone for the drug with two changes to it.
First they altered the structure to lower the amount that can pass the blood-brain barrier. This avoided any psychiatric side effects that limit the use of the original drug, ibipinapant, in the clinic. Secondly, they added a molecular group that inhibits the molecule iNOS, an enzyme responsible for promoting inflammation.
“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,” said George Kunos, who heads the study, in an NIH news release. “It is also an important factor in alcoholic liver disease, viral hepatitis, fatty liver disease, and other pathologies that promote liver fibrosis.”
In two well-established models of liver fibrosis, the NIH group found that their compound worked better to reduce fibrosis than using either CB-1 receptor inhibition or iNOS delivery alone.
Preliminary studies in their lab demonstrate no “off target” effects that might give rise to side effects, at least in their animal models. Kunos admits that the compound will need to be further tested in animal models before it's taken forward to clinical trials.