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Development of endothelin receptor antagonists as potential therapeutic agents

Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, is associated with several disease states including pulmonary hypertension, systemic hypertension and heart failure. There are two endothelin (ET) receptor subtypes known as ETA and ETB. Selective ETA receptor antagonists, as well as non-selective (dual) ETA/ETB antagonists, represent a new therapeutic target for disease states associated with elevated ET-1 levels. In vivo studies and early phase clinical trials have provided strong evidence that these agents are effective in the treatment of heart failure, essential hypertension, pulmonary hypertension and atherosclerosis. FDA approved the use of the orally active dual antagonist bosentan (Tracleer™, Roche Holding AG) for primary pulmonary hypertension in 2001. Despite important advances in this field, the complexity of biological effects mediated by two different receptor subtypes complicates the use of selective versus dual ET receptor antagonists. The number of patent applications filed in recent years emphasises the importance of this emerging class of therapeutics. From 1997 to date, ∼ 192 patents have been filed. In this review, compounds patented between 1999 and 2002 will be reviewed and clinical implications will be discussed.