Bosentan derivative may safely and effectively treat PAH, study finds

Alternatives sought due to treatment's toxicity with long-term use

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

Share this article:

Share article via email
This illustration shows a hand holding a mouse, with test tubes nearby.

Scientists in India have developed derivatives of bosentan — the active ingredient in Tracleer — that were able to ease signs of pulmonary arterial hypertension (PAH) in a rat model.

In addition to lowering blood pressure and restoring more normal heart and lung architecture, the molecules lowered biomarkers of cardiac dysfunction, oxidative stress, and other key PAH proteins.

One derivative showed particular promise as a treatment, including a potential for greater safety than is evident with long-term bosentan use. It deserves further study as a possible PAH treatment, the scientists wrote.

The study, “Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension,” was published in the European Journal of Medicinal Chemistry.

Recommended Reading
Banner image for

A reliable healthcare team helps me manage my PH and CKD

Bosentan effective PAH treatment, but long-term use can pose risks

Bosentan is a blocker, or antagonist, of endothelin receptors. Normally, when the endothelin-1 (ET-1) protein binds to these receptors, it initiates blood vessel constriction. People with PAH produce too much ET-1, which contributes to the blood vessel narrowing that characterizes the disease.

By blocking the interaction between ET-1 and endothelin receptors, bosentan helps blood vessels to relax, increasing blood flow.

Bosentan has been used for decades to improve exercise capacity and prevent clinical worsening in PAH patients. Tracleer, marketed by Janssen, was approved in the U.S.  for certain adults with PAH in 2001, and its label since has expanded to include children, ages 3 and older with idiopathic or congenital PAH. A number of generic versions of bosentan are also available.

Long-term use of bosentan, however, is linked to a range of potentially serious side effects, particularly liver damage, for which it comes with a boxed warning. It can be prescribed only to patients enrolled in a restricted distribution plan called the Bosentan Risk Evaluation and Mitigation Strategy (REMS) program.

Researchers worked to develop derivatives of bosentan that might have an enhanced therapeutic and/or safety profile. They synthesized a series of such molecules, three of which showed the most potent ability to bind to endothelin receptors and block ET-1 in lab studies.

These three derivatives were tested in a rat model of PAH, and showed a range of therapeutic effects.

Rats in this model exhibit characteristic signs of PAH, including elevated pressure in the blood vessels of the lungs and right ventricular hypertrophy, enlargement of the heart’s right ventricle due to the high vessel pressure. Treatment with all three bosentan derivatives eased these signs of PAH.

“Results indicated that the administration of selected bosentan derivatives might be an effective strategy to treat PAH,” the researchers wrote.

In lung tissue, the bosentan derivatives led to a more normal lung architecture and reduced the thickening of artery walls.

Molecule called 16h has potential for efficacy with lower likelihood of toxicity

The bosentan-like molecules also were found to lower levels of a range of biomarkers that were elevated in the PAH model, including ones associated with cardiac dysfunction and oxidative stress, a type of cellular damage implicated in PAH and many other cardiovascular diseases.

Markers of antioxidant activity — which combats oxidative stress and is impaired in PAH — rose with treatment.

These findings, the scientists wrote, support “the antioxidant potential of [the bosentan derivatives] as pulmonary and cardioprotective agents.”

Changes in gene activity and proteins associated with biological pathways known to be dysregulated in PAH were observed in the rat model, including an increase in endothelin receptor gene activity.

Several of these changes were normalized, in part, by treatment with the bosentan derivatives. The changes could help in understanding how these molecules might work as therapies, the scientists noted.

While all three compounds exhibited most or all of these benefits in the rat model, a derivative called 16h was the most promising.

That compound also had favorable pharmacological properties, a measure of how a drug affects a living being, and it was thought to be the least toxic or damaging. While liver toxicity was seen as possible, it was likely only at high doses.

“In conclusion, derivative 16 h could act as a reliable [endothelin] receptor antagonist and requires further exploration to attain its therapeutic utility in PAH management,” the scientists wrote.

A Conversation With Rare Disease Advocates