S 17162 is a novel selective inhibitor of big ET-1 responses in the rat

Endothelin-1 (ET-1) is a powerful renal vasoconstrictor peptide that may be implicated in acute renal failure. The aim of the present study was to test the effects of the novel endothelin-converting enzyme inhibitor S 17162 (N-(2,3 dihydroxy propyl phosphonyl)-(S)-Leu-(S)-Trp-OH, disodium salt) on pressor responses to ET-1 and its precursor, big ET-1, in isolated perfused rat kidneys and in pithed rats. In both models, phosphoramidon selectively inhibited the pressor responses to big ET-1 without influencing those to ET-1, angiotensins (AT-I and AT-II) or norepinephrine. S 17162 was active against big ET-1 in both test systems. It selectively inhibited the pressor responses to big ET-1 with ID50 values of 160 micrograms/kg/min (phosphoramidon: 120 micrograms/kg/min) in the spinal rat and 6 microM (phosphoramidon: 5 microM) in the perfused rat kidney. In the nonanesthetized rat, S 17162 at 20 mg/kg p.o. inhibited the pressor responses to big ET-1, demonstrating its oral bioavailability. Therefore, S 17162 is a potential candidate for development as an orally active anti-endothelin drug.