Inhibition of big ET-1-induced pressor response by an orally active dual inhibitor of endothelin-converting enzyme and neutral endopeptidase 24.11.

The pharmacologic properties of CGS 26393, a prodrug of the endothelin-converting enzyme/neutral endopeptidase 24.11 inhibitor CGS 26303, were examined in conscious Sprague-Dawley rats. After oral administration of CGS 26393 at 30 mg/kg, the free concentrations of CGS 26303 in plasma were calculated to be 1.7 +/- 0.3, 1.2 +/- 0.2, and 0.31 +/- 0.05 microM at 4, 8, and 24 h, respectively. CGS 26393 inhibited the pressor response produced by exogenous big ET-1 in a dose-dependent manner. A 70% inhibition of the pressor response was observed when the prodrug was administered at 30 mg/kg p.o. As predicted by its pharmacokinetics, the inhibitory activity of CGS 26393 persisted for up to 8 h. These findings demonstrate that CGS 26393 in an orally active, long-acting ECE inhibitor in vivo.