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.
Trapani
A J
AJ
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901, USA.
De Lombaert
S
S
Kuzmich
S
S
Jeng
A Y
AY
D000284:Administration, Oral; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects*; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors*; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*
D019332:Endothelin-1; D016232:Endothelins; D063065:Organophosphonates; D011480:Protease Inhibitors; D011498:Protein Precursors; D013777:Tetrazoles; C098285:CGS 26393; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes