# Systemically restricted 5-HT2B antagonists for pulmonary arterial hypertension

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $637,320

## Abstract

PROJECT SUMMARY/ABSTRACT
Pulmonary arterial hypertension (PAH) is a progressive lethal disease characterized by widespread obstruction
in the smallest arteries of the lungs. Pulmonary microvascular obstruction leads to increased pulmonary vascular
resistance, which subsequently causes right heart failure. Potential new targets for PAH therapy are lacking, yet
despite the existing need for disease-modifying therapeutics, the rational selection of targets is significantly
hampered by the still poor understanding of the cellular and molecular mechanisms that mediate PAH
pathogenesis. We have shown in multiple animal models of PAH that targeting the serotonin 2B receptor (5-
HT2B) genetically and pharmacologically prevents the development of disease. While 5-HT2B antagonism
shows tremendous promise for PAH therapy, currently embodiments penetrate the blood-brain barrier. 5-HT2B
mutation in the central nervous system is associated with several adverse consequences, such as depression,
aggression, impaired sleep, and suicidality that limit the clinical potential of this treatment. Therefore, to
overcome this limitation we have developed novel 5-HT2B antagonists that are both selective and potent, but
also systemically restricted such that they do not cross the blood-brain-barrier. Here, we propose to de-risk these
compounds for clinical translation through lead compound selection, safety and toxicity studies, and finally
efficacy in preclinical models. At the conclusion of these aims, we hope to have identified a well-positioned,
disease-modifying PAH therapy that has completed IND-enabling studies.

## Key facts

- **NIH application ID:** 10808479
- **Project number:** 1R01HL172247-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** William D Merryman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $637,320
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808479

## Citation

> US National Institutes of Health, RePORTER application 10808479, Systemically restricted 5-HT2B antagonists for pulmonary arterial hypertension (1R01HL172247-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10808479. Licensed CC0.

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