ABSTRACT

The endogenous endothelins 1 (ET-1, -2, and -3), a family of homologous 21-amino acid isopeptides, possess exceptionally potent vasoconstrictory activity and play an important role in the control of vascular smooth muscle tone and blood flow. Characterization of elevated endothelin levels in a variety of disease states has promoted an intense effort by a number of pharmaceutical companies to identify potent and selective nonpeptide endothelin antagonists of different subtype selectivity for the two-endothelin receptors ETA and ETB. Indications that have been targeted include congestive heart failure, pulmonary hypertension, angina, chronic renal failure, restenosis, and cancers.