Pursuing a hopeful cure for PAH

Getty Images 1633111221

Two researchers have developed a new experimental drug to treat pulmonary arterial hypertension (PAH). The cutting-edge compound, VU6047534, targets serotonin 2B receptors without crossing the blood-brain barrier and causing neurological side effects.  

David Merryman, PhD, and Craig Lindsley, PhD, who have been collaborating since 2018, published a new article on their therapeutic approach in the September issue of the Journal of the American College of Cardiology: Basic to Translational Science. Dr. Merryman is a professor of biomedical engineering, pharmacology and medicine at Vanderbilt University. Dr. Lindsley is the William K. Warren, Jr. professor of medicine and professor of pharmacology, biochemistry and chemistry at Vanderbilt University, as well as director of the Warren Center for Neuroscience Drug Discovery (WCNDD) in Tennessee.

The research team’s most recent study evaluated the efficacy of VU6047534 on mice. It exposed mice models with and without PAH to hypoxia (low oxygen levels) and introduced a chemical called sugen 5416. The study found that the experimental drug reduced heart strain in the mice without altering the brain. 

Drs. Merryman and Lindsley, along with their research team, first presented results of their work in 2021. They demonstrated that inhibiting certain serotonin 2B receptors located in the fibroblasts of the lungs and heart (5-HT2B, in particular) allows the organs to heal and may even help reverse damage caused by a heart attack. 

To validate this, the researchers created and tested more than 200 possible compounds in search of one that would target the activity of 5-HT2B and simultaneously avoid reaching the brain or affecting other critical serotonin 2B receptors. 

“We modified some existing serotonin 2B antagonists to make them more specific to the receptors in the heart that we were focused on,” said Dr. Merryman. “We identified a compound that won’t penetrate the brain in humans.”

Currently, there is no cure for PAH, only therapeutic options that help relieve symptoms. This research, funded by the National Institutes of Health (NIH) and a Vanderbilt University Discovery Grant, will allow the team at WCNDD to refine the drug for use in humans and conduct clinical trials. 

“I’m pleasantly surprised that we were able to engineer VU6047534 such that it stays out of the brain while we made it a much more selective compound that doesn’t hit the other serotonin receptors,” Dr. Merryman said. “It doesn’t show any binding to the other serotonin receptors, which is a rare feat in drug development.”

More in Pulmonary
Page 1 of 16
Next Page