Endothelin research and the discovery of macitentan for the treatment of pulmonary arterial hypertension.

Endothelin receptor antagonists (ERAs) are used for the treatment of pulmonary arterial hypertension (PAH). Macitentan, a dual (ET+ET) ERA approved for the long-term treatment of PAH, was discovered through a tailored research program aimed at improving efficacy and safety over the existing ERAs. The goal of improved efficacy was based on the understanding that not only the ET receptor but also the ET receptor contributed to the hemodynamic and structural changes induced by endothelin-1 (ET-1) in pathological conditions and on the predefined requirements for optimal tissue penetration and binding kinetics of the antagonist. The goal of improved safety was based on the discovery of the role of ET receptors in vascular permeability and vasopressin release and on the elucidation of the mechanism by which bosentan (the first approved oral dual ET/ET ERA) caused liver enzyme changes. Our intention was to design a molecule that would block ET and ET receptors optimally and would not interfere with bile salt elimination. This review takes us through the drug discovery journey that led to the discovery, development, and registration of macitentan.