Aprocitentan

Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system. It is produced constitutively by vascular endothelial cells to maintain vascular tone and is found in a variety of other cells including vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, neurons, and epithelial cells in the lungs and kidneys. ET-1 acts on two receptors, ETA and ETB, located on vascular smooth muscle cells and endothelial cells which serve to regulate blood pressure by inducing vasoconstriction or vasodilation. ET-1 is an extremely potent vasoconstrictor that works primarily via interactions with the ETA receptor and, under pathologic conditions, further induces vasoconstriction via interactions with ETB2. The overexpression of both ET-1 and ET receptors has been shown in a variety of pathologies, including essential hypertension, pulmonary arterial hypertension, chronic kidney disease, and diabetes mellitus.

Aprocitentan is a dual endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors. This inhibition mitigates the hypertensive effects of ET-1 overexpression, including endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.