Next-generation therapeutics and renaissance of legacy drugs targeting the endothelin system

Endothelin-1 (ET-1) was discovered in 1988, followed by identification of ET_A and ET_B receptors in 1990, enabling rapid development of the first endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) for pulmonary arterial hypertension, a condition marked by elevated ET-1. Nearly a decade later, a new therapeutic wave began with the ET_B agonist sovateltide (2021) for cerebral ischemic stroke, demonstrating the benefits of ET_B activation. More recent antagonist development has shifted toward ET_A-selective agents to preserve ET_B function. Clazosentan (ET_A) for cerebral vasospasm and aprocitentan (ET_A/ET_B) for resistant hypertension extended endothelin-targeted therapy into more common diseases. In kidney disease, sparsentan (AT₁/ET_A) and atrasentan (ET_A) have both been approved for IgA nephropathy, with atrasentan succeeding after earlier failed trials. Repurposing has become a major strategy in G protein-coupled receptor drug development. This review outlines approaches for identifying legacy endothelin compounds suitable for new indications, using zibotentan, now combined with dapagliflozin to reduce fluid retention as an example. Kidney disease remains a central focus of current trials, which include new ET_A-selective diosuxentan and monoclonal antibody getagozumab, and the ET_B peptide antagonist vodudeutentan. The review summarizes recent pharmacology and clinical data and highlights emerging strategies for next-generation endothelin-pathway therapeutics.