title: CGS 34043: a non-peptidic, potent and long-acting dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11.
abstract: Endothelin-1 (ET- 1) is a potent vasoconstrictor. Its biosynthesis is catalyzed by endothelin converting enzyme (ECE). In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic, and it is mainly degraded by neutral endopeptidase 24.11 (NEP). Therefore, compounds that can suppress the production of ET-1 by inhibiting ECE while simultaneously potentiating the levels of ANP by inhibiting NEP may be novel agents for the treatment of cardiovascular and renal dysfunction. CGS 34043 is one such compound, which inhibited the activities of ECE-1a and NEP with IC50 values of 5.8 and 110 nM, respectively. In vivo, it inhibited the pressor response induced by big ET-1, the precursor of ET-1, dose-dependently in rats, and the inhibition was sustained for at least 2 hr. In addition, CGS 34043 increased plasma ANP by 150% up to 4 hr after an intravenous dose of 10 mg/kg in conscious rats infused with ANP. However, this compound had no effect on the angiotensin I-induced pressor response. These results demonstrate that CGS 34043 is a potent and long-lasting dual inhibitor of ECE-1 and NEP. Consequently, it may be beneficial for the treatment of diseases in which an overproduction of ET-1 and/or enhanced degradation of ANP plays a pathogenic role. The activity of CGS 34753, an orally active prodrug of CGS 34043, is also described.
authors.affiliation: Novartis Institute for Biomedical Research, Summit, NJ 07901, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: S
authors.initials: S
authors.lastname: De Lombaert
authors.forename: M E
authors.initials: ME
authors.lastname: Beil
authors.forename: C W
authors.initials: CW
authors.lastname: Bruseo
authors.forename: P
authors.initials: P
authors.lastname: Savage
authors.forename: M
authors.initials: M
authors.lastname: Chou
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; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007672:Kidney Cortex / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C404931:CGS 34043; C412663:CGS 34753; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; D011498:Protein Precursors; D013777:Tetrazoles; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes