title: Pharmacological properties of CGS 35066, a potent and selective endothelin-converting enzyme inhibitor, in conscious rats.
abstract: The purpose of this study was to examine the pharmacologic properties of CGS 35066, a novel aminophosphonate inhibitor of endothelin-converting enzyme-1 (ECE-1). CGS 35066 inhibited the activity of human ECE-1 and rat kidney neutral endopeptidase 24.11 (NEP) in vitro with IC50 values of 22 +/- 0.9 nM and 2.3 +/- 0.03 microM, respectively. The in vivo effects of CGS 35066 were characterized in conscious, catheterized rats. At 30 and 120 min after treatment with vehicle, big endothelin-1 (big ET-1, 0.3 nmol/kg i.v.) produced increases in mean arterial pressure (MAP) of 982 +/- 31 and 992 +/- 43 mmHg x min (area under the curve), respectively. Doses of 0.3, 1.0, 3.0 and 10.0 mg/kg i.v., of CGS 35066 blocked these pressor responses by 61 +/- 7, 78 +/- 4, 93 +/- 4 and 98 +/- 2% at 30 min (p < 0.05 compared with vehicle controls, all doses), and by 29 +/- 7, 63 +/- 5, 63 +/- 5 and 84 +/- 10% at 120 min (p < 0.05, all doses). In contrast, the pressor effect (58 +/- 6 mmHg) of angiotensin-I (300 ng/kg i.v.) was unaffected by the ECE-1 inhibitor (10 mg/kg i.v.) indicating the absence of activity against angiotensin-converting enzyme. In rats infused with atrial natriuretic peptide (ANP), CGS 35066, at 1 mg/kg, had no effect on plasma irANP; however, irANP levels were doubled at a dose of 30 mg/kg. These results demonstrate that CGS 35066 is the most potent and selective ECE inhibitor identified to date.
authors.affiliation: Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: M E
authors.initials: ME
authors.lastname: Beil
authors.forename: C W
authors.initials: CW
authors.lastname: Bruseo
authors.forename: S
authors.initials: S
authors.lastname: De Lombaert
authors.forename: A Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D009320:Atrial Natriuretic Factor / Q000097:blood; D001572:Benzofurans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors; D063065:Organophosphonates / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001572:Benzofurans; C404932:CGS 35066; D063065:Organophosphonates; D011480:Protease Inhibitors; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes