Parkinson's drug Pimavanserin may help treat NAFLD, finds study

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by excessive fat accumulation in the liver that can lead to serious complications, including nonalcoholic steatohepatitis, cirrhosis, and cancer.

At present there is a dearth of drugs to treat NAFLD, with current therapies revolving around lifestyle interventions.

Researchers at Gwangju Institute of Science and Technology, Korea have found that serotonin antagonist Pimavanserin may help treat NAFLD by regulating lipid metabolism in the liver. Pimavanserin is drug approved for the treatment of Parkinson's.

The findings of the study have been published in the Journal of Medicinal Chemistry.

Prof Jin Hee Ahn lead author says, "NAFLD is a serious public health problem worldwide. However, no pharmacological agents have been specifically approved for its treatment yet."

For their study, the scientists focused on a well-known neurotransmitter called serotonin. Serotonin is widely known as the "happy" neurotransmitter, and its deficiency in the central nervous system (CNS) can cause various brain disorders. But, not many know that it is also found in the gastrointestinal tract; here, it is called "peripheral" serotonin, which has different functions altogether, such as regulating lipid metabolism in the liver.

In a previous study published in Nature Communications, Prof Hail Kim, the co-corresponding author of this study, had investigated peripheral serotonin as a drug target with knockout mice models (mice lacking functional peripheral serotonin). This study reported that these mice showed reduction in liver weight, hepatic lipid accumulation, and hepatic triglyceride content and improved NAFLD activity.

These findings formed the basis of Prof Ahn's study and prompted the research group to identify new peripheral serotonin antagonists. The scientists selected a CNS drug approved for the treatment of Parkinson's, called pimavanserin. Pimavanserin acts as an "antagonist" to serotonin, mimicking its effect in the CNS. The scientists then structurally modified this drug such that it cannot permeate the blood-brain barrier, by adding different types of molecules to it. In this way, they generated an array of novel compounds. On testing these, the scientists found one compound in particular to show promising results: it showed very low blood-brain barrier permeation and thus had the potential to target peripheral serotonin systems.

The scientists tested this compound in obese mice with impaired liver function. Interestingly, the mice showed improvement in symptoms of fatty liver disease, such as improved glucose tolerance. Additionally, their body fat decreased while lean body mass increased. Prof Ahn says, "Through the chemical optimization of an existing drug, pimavanserin, we identified a new peripheral agent for the possible treatment of NAFLD."

Although this novel compound is yet to be tested in humans, these findings show that it has remarkable potential in treating fatty liver disease. Optimistic about these findings, Prof Ahn concludes, "We hope that our novel drug candidate will offer relief to patients bearing the brunt of NAFLD."

For further reference log on to:

J.Med. Chem. 2020, 63, 8, 4171–4182

https://doi.org/10.1021/acs.jmedchem.0c00002