[Endothelin: From discovery to pharmacotherapeutic innovations]

Abstract

Objectives: Endothelin (ET) is a major therapeutic target in cardiopulmonary diseases. The purpose of this review is to present the main concepts concerning ET biology, its pathophysiological roles and the major pharmacological and medical advances recently developed around the concept of ET receptor blockade.

Methods: Analysis of PubMed database (keywords: endothelin, endothelin receptor antagonists, pulmonary hypertension, etc.), and of abstract originating from recent international meetings.

Results: ET is a peptide produced by vascular endothelial cells as well as by many other tissues. Both its production and its effects are activated in pathological situations associated with endothelial dysfunction. ET is characterized by a strong tropism toward tissues because of its polarized release, the strong tissue receptor density and high affinity of the receptors for the peptide. ET exerts several vascular effects, including vasoconstriction, proliferation and hypertrophy, as well as non-vascular effects, notably stimulation of cardiac hypertrophy, tissue fibrosis and inflammation. Both vascular and non-vascular effects depend on the stimulation of two receptor subtypes, ETA and ETB. ET receptor antagonists (ERA) demonstrated beneficial effects in many different pre-clinical models of cardiovascular and pulmonary diseases, and constitute a first-line treatment of patients with pulmonary arterial hypertension (PAH). Recently, the targeted search for a novel ERA led to the development of macitentan which, compared to existing ERA, show optimized tissue penetration, increased receptor affinity and in vivo pharmacological efficacy in pre-clinical models, associated with a favorable profile, in terms of hepatic safety and drug interactions. The clinical efficacy of macitentan in the treatment of PAH was recently demonstrated in the SERAPHIN trial, which contrasts with previous PAH trials because of its long duration, the high number of patients enrolled, and its primary endpoint evaluating morbidity/mortality. Results show a significant reduction of the primary composite morbidity/mortality endpoint (taking into account both progression of PAH and death) by 30 and 45% with macitentan 3 and 10mg, respectively, compared to placebo, and confirm on the large scale the favorable tolerance profile, especially at the hepatic level.

Conclusion: The extensive knowledge on the complexity of the ET system allowed the synthesis of a new antagonist optimized, in terms of pharmacological efficacy and safety, which also show promising therapeutic effects in PAH patients, with demonstrated results in a prospective study using a composite primary endpoint of morbidity-mortality.