Nonpeptidic endothelin-converting enzyme inhibitors and their potential therapeutic applications.
Endothelins (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase 24.11 (NEP), another metalloprotease. Therefore, it is not surprising that the majority of ECE inhibitors also possess potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors. Potential clinical applications of these compounds in hypertension, chronic heart failure, restenosis, renal failure, and cerebral vasospasm deduced from studies with relevant animal models are reviewed.
Jeng
Arco Y
AY
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. arco.jeng@pharma.novartis.com
Mulder
Paul
P
Kwan
Aij-Lie
AL
Battistini
Bruno
B
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000201:enzymology; D008666:Metalloendopeptidases; D009422:Nervous System Diseases / Q000188:drug therapy / Q000201:enzymology
D004791:Enzyme Inhibitors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes