Chapter 8. Recent advances in endothelin antagonism

Abstract

Publisher Summary This chapter presents an overview of advances in endothelin antagonism. The endothelins (ET-1, ET-2 and ET-3), a family of 21-amino acid peptides are potent, long-acting constrictors of vascular smooth muscle and are also potent mitogens. Aided by known endothelin antagonists, investigators have identified the possible involvement of abnormally high plasma or tissue levels of ET-1, the predominant isoform of ET, in a diverse array of clinical syndromes, including systemic and pulmonary hypertension, cardiac and renal failure, cerebral vasospasm, restenosis, and prostate cancer. Potent and selective endothelin converting enzyme (ECE) inhibitors are now available, so are those inhibiting neutral endopeptidase (NEP) and ACE concomitantly. A large number of highly potent, orally available, balanced or selective, long or short acting ET antagonists have been discovered, many of which are currently in clinical trials. The chapter focuses on advances in discovering novel endothelin inhibitors since 1998. Endothelin biosynthesis and ECE inhibitors are explained and an overview of endothelin receptors and ET receptor antagonists is presented. Structure of P2X receptors is also described.