title: Endothelin research and the discovery of macitentan for the treatment of pulmonary arterial hypertension.
abstract: Endothelin receptor antagonists (ERAs) are used for the treatment of pulmonary arterial hypertension (PAH). Macitentan, a dual (ETA+ETB) 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 ETAreceptor but also the ETBreceptor 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 ETBreceptors in vascular permeability and vasopressin release and on the elucidation of the mechanism by which bosentan (the first approved oral dual ETA/ETBERA) caused liver enzyme changes. Our intention was to design a molecule that would block ETAand ETBreceptors 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.
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals, Allschwil, Switzerland Martine.clozel@actelion.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage*; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology*; D011743:Pyrimidines / Q000008:administration & dosage*; D017466:Receptors, Endothelin / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011743:Pyrimidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; C533860:macitentan
keywords: bosentan; discovery; endothelin; macitentan; pulmonary arterial hypertenstion