Arco Y. Jeng* and Stephane De Lombaert Pages 597 - 614 ( 18 )
Endothelins (ETs) are a family of potent, peptidic vasoconstrictors and are implicated in the involvement of a variety of cardiovascular, renal, and central nervous system diseases. The final step of post-translational processing of these peptides is catalyzed by endothelin converting enzyme (ECE), a zinc metalloprotease. Inhibitors of this enzyme are expected to suppress the biosynthesis of ETs and provide an alternate approach to the ETA/ETB receptor antagonism. The biochemical characteristics of ECE are briefly reviewedin this article. The main focus is on the design and pharmacological properties of various classes of ECE inhibitors, including peptides, natural products, and low molecular weight molecules featuring a phosphorus-containirrg functionality, a sulfhydryl, a hydroxamic acid, or a carboxylic acid as the zinc-binding group. Compounds such as phosphoramidon, CGS 26303, and SCH 54470 have been shown to be efficacious in experimental models of hypertension, chronic heart failure, cerebral vasospasm following subarachnoid hemorrhage, and renal failure. Thus, ECE inhibitors may represent a new class of agents for the treatment of diseases where an overproduction of ETs plays a pathogenic role.