Endothelin-converting enzyme inhibitors and their potential for cardiovascular and renal therapeutics

Abstract

Inhibition of endothelin-converting enzyme (ECE) will reduce the levels of endothelin-1 (ET-1). A pathological effect for ECE/ET-1 on the human cardiovascular system has been suggested in systemic hypertension, pulmonary hypertension, chronic heart failure, myocardial infarction, atherosclerosis and restenosis. On the kidney, ECE/ET-1 may have a pathological role in acute and chronic renal failure, IgA nephropathy, cyclosporin toxicity, chronic renal allograft rejection and autosomal-dominant polycystic kidney disease. ECE-1 inhibitors have therapeutic potential in all of these cardiovascular and renal conditions. Selective non-peptide ECE inhibitors that have been patented include FR-901533, PD-069185, CGS-35066, SM-19712, CGS-30084 and Ro0677447. Studies with animal disease models suggest that ECE inhibitors may have a role in the treatment of pulmonary hypertension, myocardial infarction, cardiac hypertrophy and failure, restenosis and acute renal failure. There are four isoforms of ECE-1 with similar catalytic activity but differences in tissue and cellular localisation. The development of selective inhibitors of the ECE-1 isoforms may give better targeting of function/disease than the presently available ECE inhibitors.