Effects of metalloprotease inhibitors on smooth muscle endothelin-converting enzyme activity.

The enzyme responsible for the conversion of exogenous big endothelin-1 to endothelin-1 by porcine coronary arterial smooth muscle has been shown to be a metalloprotease. The potencies of eight metalloprotease inhibitors for this endothelin-converting enzyme were determined. CGS 25015, CGS 26129, and thiorphan inhibited the enzyme activity monophasically with IC50 values of 2.6, 2.4, and 190 microM, respectively. In contrast, the data obtained using phosphoramidon as an inhibitor were best fit by a two-site model. The biphasic concentration-response curve had IC50 values of 4.6 microM and 2.2 mM. Three analogs of phosphoramidon were also tested for enzyme inhibition. Removal of the rhamnose moiety of phosphoramidon reduced the potency (IC50 = 15 microM), whereas substitution of the rhamnose by N-[2-(2-naphthyl)ethyl] improved the potency (IC50 = 2.0 microM). These results identify a thiol and a phosphonyl series of compounds as smooth muscle endothelin-converting enzyme inhibitors. The structure-activity relationships revealed that an aromatic or aliphatic group in the P2' position or an aromatic group in the P1 position of the inhibitor significantly increased the potency.