title: Characterization of CGS 31447, a potent and nonpeptidic endothelin-converting enzyme inhibitor.
abstract: Optimization of an aminophosphonic acid series of compounds for inhibition of endothelin-converting enzyme (ECE) has led to the discovery of CGS 31447. This compound reversibly inhibited the activity of recombinant human ECE-1 with an IC50 value of 21 nM. The effect of CGS 31447 was not due to nonspecific chelation of the zinc ion at the catalytic center of ECE-1 by the phosphonic acid of the inhibitor. Determination of kinetic parameters of ECE-1 in the presence of 5-15 nM CGS 31447 revealed the competitive nature of the compound; a K1 of 7 nM was obtained. CGS 31447 infused at concentrations of 0.01, 0.1, and 1.0 microM inhibited the mean increase in big ET-1-induced pressor responses in isolated and perfused rat kidneys by 7, 39, and 68%, respectively, compared with the controls. These results demonstrate that CGS 31447 is a potent, reversible, and competitive inhibitor of ECE-1.
authors.affiliation: Research Department, Novartis Pharmaceuticals Corporation, Summit, NJ 07901, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Shetty
authors.forename: P
authors.initials: P
authors.lastname: Savage
authors.forename: D
authors.initials: D
authors.lastname: DelGrande
authors.forename: S
authors.initials: S
authors.lastname: De Lombaert
authors.forename: A Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D063065:Organophosphonates / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C113055:CGS 31447; D019332:Endothelin-1; D016232:Endothelins; D063065:Organophosphonates; D011480:Protease Inhibitors; D011498:Protein Precursors; D011994:Recombinant Proteins; D013777:Tetrazoles; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes