Characterization of CGS 31447, a Potent and Nonpeptidic Endothelin-Converting Enzyme Inhibitor

Abstract

Summary:

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 μM 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.