Chapter 7. Endothelin Inhibitors

Abstract

Publisher Summary Discovery and development of endothelin inhibitors have been one of the fastest growing research areas in the pharmaceutical industry. With several newly discovered endothelin (ET) inhibitors, investigators soon confirmed the possible involvement of endothelin-1 (ET-1) in number of disease states, including systemic hypertension (HP), pulmonary hypertension (PH), renal and myocardial ischemia (RI and MI), stroke, subarachnoid hemorrhage (SAH), restenosis (RT), congestive heart failure (CHF), and chronic renal failure (CRF). Currently, several ET receptor antagonists have been brought to the early development stages with a few already having advanced into clinical evaluation. Although less advanced, persistent effort in ECE inhibitor area has led to the discovery of several novel inhibitors. This chapter reviews recent progress in the discovery and development of new endothelin converting enzyme (ECE) inhibitors and ET receptor antagonists with a brief introduction of the endothelin system. The production of ET-1 with ECE inhibitors have been the subject of much research. The physiologically relevant ECE is a membrane-bound metalloprotease that is inhibited by phosphoramidon (PA), a nonselective peptidic metalloprotease inhibitor, but is insensitive to the inhibitors of other metalloproteases, such as thiorphan and captopril (angiotensin converting enzyme). Phosphoramidon inhibits both ECE-1 and ECE-2 albeit, with a 250-fold difference in potency. It also potently inhibits other metalloproteases, such as neutral endopeptidase (NEP), with IC 50 values in the low nanomolar range. Another example is thiorphan that is a potent NEP inhibitor but is inactive against ECE-1 and ECE-2. Selective mass screening of zinc protease inhibitors revealed an analog of retrothiorphan to be moderately active to ECE-1. Such ECE inhibitors and ET antagonists of diverse structural types have been identified and optimized with different profiles in terms of potency, selectivity, efficacy, and pharmacokinetics.