title: S 17162 is a novel selective inhibitor of big ET-1 responses in the rat.
abstract: 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.
authors.affiliation: Servier Research Institute, Division of Angiology, Suresnes, France.
authors.forename: J J
authors.initials: JJ
authors.lastname: Descombes
authors.forename: P
authors.initials: P
authors.lastname: Mennecier
authors.forename: D
authors.initials: D
authors.lastname: Versluys
authors.forename: V
authors.initials: V
authors.lastname: Barou
authors.forename: G
authors.initials: G
authors.lastname: de Nanteuil
authors.forename: M
authors.initials: M
authors.lastname: Laubie
authors.forename: T J
authors.initials: TJ
authors.lastname: Verbeuren
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases; D009638:Norepinephrine / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology*; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004151:Dipeptides; D019332:Endothelin-1; D016232:Endothelins; C098284:N-(2,3-dihydroxypropylphosphonyl)leucyl-tryptophan disodium salt; D063065:Organophosphonates; D011480:Protease Inhibitors; D011498:Protein Precursors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D009638:Norepinephrine