Antifibrotic Therapy for the Treatment of Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive condition affecting the heart and lungs. It is characterized by abnormally high blood pressure (hypertension) in the pulmonary artery that carries blood from the heart to the lungs. The most common symptoms are shortness of breath during exertion and fainting spells, and as the condition worsens, patients can experience dizziness, swelling of the lower extremities, chest pain, and a racing pulse. Forms of PAH are classified based upon the underlying cause of disease, which guides treatment. However, effective treatments are lacking for patients whose condition is driven by fibrotic processes that damage the lungs. The lead collaborators identified a compound that improved the hypertension and fibrosis in animal models of PAH. The goal of this project was to optimize the compound for further preclinical development.

Scientific Synopsis

Relaxin was originally discovered as a hormone of pregnancy, promoting cardiovascular and renal adjustments to meet the increased nutritional demands of the growing fetus, the elevated requirements for renal clearance of metabolic wastes, and the relaxation of smooth muscle and ligaments to facilitate labor and delivery. The relaxin/insulin-like family peptide receptor 1 (RXFP1) has both antifibrotic and vasodilatory effects when stimulated by relaxin. While recombinant relaxin has been explored clinically for various diseases, its short half-life and requirement for intravenous delivery present obstacles for longer-term use.

To circumvent these limitations, the lead collaborators identified a synthetic small molecule agonist of RXFP1 (ML290) as an alternative to relaxin hormone. In an animal model of chemically-induced fibrosis, ML290 was shown to reverse fibrotic damage. In a second animal model of hypoxia-conditioned PAH, ML290 was shown to reduce right ventricular systolic pressure and attenuate right ventricular hypertrophy after intraperitoneal administration. These observations supported the hypothesis that a small molecule RXFP1 agonist could be useful to treat PAH in patients with idiopathic pulmonary fibrosis.

Lead Collaborator

Florida International University, Miami, Florida
Alexander Agoulnik, Ph.D.

Public Health Impact

The dual antifibrotic and vasodilatory effects of a single compound (ML290 or a derivative) represented a more comprehensive approach to treating this challenging condition. In addition to PAH, such a compound also could have wider applications for other fibrotic conditions in other organs, such as liver, skin and kidney.


TRND scientists completed a medicinal chemistry campaign to optimize ML290, identifying a series of agonists with the desired in vitro pharmacological profile and improved drug-like properties and pharmacokinetics after oral administration. However, after careful study in animal models, it became apparent that there was a disconnect between the in vitro activities of the ML290 series and the in vivo efficacy. As a result, the project was discontinued.