Endothelin system drugs see renaissance: ETA/ETB antagonists and agonists expand indications for hypertension, kidney disease, and stroke

The endothelin system, comprising ET-1 and its ETA and ETB receptors, plays a critical role in cardiovascular and renal physiology. Dysregulation, particularly elevated ET-1, contributes to conditions like pulmonary arterial hypertension (PAH), where current treatments often fall short. Early endothelin receptor antagonists (ERAs) like bosentan targeted both receptors, but newer strategies aim for ETA-selectivity or ETB activation to optimize therapeutic profiles and minimize side effects, addressing unmet needs in more common diseases beyond PAH.

This comprehensive review synthesizes recent pharmacological and clinical data on endothelin-targeting therapeutics. It outlines approaches for identifying legacy endothelin compounds suitable for new indications and highlights emerging strategies for next-generation drugs. The review covers both endothelin receptor antagonists (ETA-selective and dual ETA/ETB) and ETB agonists, detailing their development, mechanisms, and clinical applications across various disease states, including cerebral ischemic stroke, cerebral vasospasm, resistant hypertension, and kidney disease.

The review details the evolution of endothelin-targeted therapies, starting with the first-generation ETA/ETB antagonists bosentan, ambrisentan, and macitentan for pulmonary arterial hypertension. A new wave began with the ETB agonist sovateltide (approved 2021) demonstrating benefits for cerebral ischemic stroke. More recent antagonist development has shifted towards ETA-selective agents, such as clazosentan for cerebral vasospasm, and the dual ETA/ETB antagonist aprocitentan for resistant hypertension, extending therapy into more prevalent conditions. In kidney disease, specifically IgA nephropathy, both the AT1/ETA antagonist sparsentan and the ETA-selective atrasentan have gained approval, with atrasentan succeeding after earlier trial failures.

Repurposing legacy drugs is a key strategy, exemplified by zibotentan, now combined with dapagliflozin to mitigate fluid retention, expanding its utility. Current trials continue to focus on kidney disease, investigating novel ETA-selective agents like diosuxentan, the monoclonal antibody getagozumab, and the ETB peptide antagonist vodudeutentan, underscoring the ongoing innovation in this therapeutic area.