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 have identified a compound that improves the hypertension and fibrosis in animal models of PAH. The goal of this project is 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 have identified a synthetic small molecule agonist of RXFP1 called 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 support the hypothesis that ML290 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

ML290 represents a novel therapeutic approach to PAH. The dual antifibrotic and vasodilatory effects of a single compound represent a more comprehensive approach to treating this challenging condition. In addition to treating PAH, a progressive fibrotic disease of the lung, this candidate may have wider applications for other fibrotic conditions in other organs, such as liver, skin and kidney.

Outcomes

TRND scientists have recently initiated a medicinal chemistry campaign to optimize ML290, with the goal of developing a new lead that is active in the mouse after oral administration.