Vanderbilt scientists make headway in drug development to cure pulmonary arterial hypertension

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Research led by David Merryman, a professor of biomedical engineering, pharmacology and medicine who holds the Walters Family Chair, has resulted in the development of VU6047534, a new drug that treats pulmonary arterial hypertension—a type of high blood pressure that affects arteries in the lungs and in the heart—without serious neurological side effects.

Merryman conducted the research with Craig Lindsley, the William K. Warren, Jr. Professor of Medicine, University Professor of Pharmacology, Biochemistry and Chemistry, and director of the Warren Center for Neuroscience Drug Discovery.

The article, “Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension,” was published in the Journal of the American College of Cardiology: Basic to Translational Science on Sept. 13.

In research published in 2021, Merryman and collaborators demonstrated that when serotonin 2B receptors are inhibited within the lungs and cardiac fibroblasts—“worker bee” cells that produce connective tissue in the heart—the organs heal significantly, and damage done by a heart attack can even be reversed.

Not every receptor can be turned off, however. Serotonin 2B receptors are also responsible for regulating serotonin in the brain, which affects mood, sleep and other key body functions. The potentially serious behavioral and neurological side effects of turning off the receptor in the brain meant the researchers needed to develop a compound with a high degree of specificity to ensure that it would not cross the blood-brain barrier. Using medicinal chemistry approaches for which the WCNDD is known, the team designed and screened more than 200 potential compounds. “We modified some existing serotonin 2B antagonists to make them more specific to the receptors in the heart that we were focused on,” Merryman said. “We identified a compound that won’t penetrate the brain in humans.”

This research paves the way for more study and enhancement of the compound and for clinical trials. Pulmonary arterial hypertension, a rare but fatal disease, does not yet have a successful cure—only treatment that lessens symptoms. The state-of-the-art compound VU6047534 represents one of just a few therapies that show promise to treat PAH.

Merryman and Lindsley have been collaborators since 2018, when the idea for a new drug that wouldn’t cross the blood-brain barrier came to light. This is the only cardiopulmonary drug discovery being conducted at the WCNDD at this time.

“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,” Merryman said. “It doesn’t show any binding to the other serotonin receptors, which is a rare feat in drug development.”

He and Lindsley are co-authors on a perspectives article, “2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery,” published in the Journal of Medicinal Chemistry. The paper explores a new understanding of how to work with the serotonin 2B receptor, in large part resulting from the drug discovery work they undertook in the development of VU6047534.

Merryman and Lindsley are pursuing the development of the compound. The research discussed in this paper was funded by the National Institutes of Health and a Vanderbilt University Discovery Grant. The Discovery Grant program is designed to serve as a catalyst for significant external funding sources, including from large federal funding agencies such as the National Science Foundation, National Institutes of Health, Department of Defense.