title: CGS 35601 and its orally active prodrug CGS 37808 as triple inhibitors of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting enzyme.
abstract: CGS 35601 is a potent triple inhibitor of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting enzyme. It inhibited the activities of these three enzymes with IC50 values of 55, 2 and 22 nM, respectively. In conscious rats, CGS 35601 suppressed the big endothelin-1-induced pressor response by 82% and 72% at 30 and 120 minutes, respectively, following injection at a dose of 10 mg/kg, intravenously. At the same dose, CGS 35601 increased plasma atrial natriuretic peptide (ANP) immunoreactivity by 170% for up to 4 hours in conscious rats infused with ANP, and it inhibited the angiotensin I-induced pressor response by 74-94% within the first 2 hours after dosing. Similar in vivo activities were also observed with its orally active prodrug, CGS 37808. This compound blocked the big endothelin-1- induced pressor response by 71% and 67% at 30 and 120 minutes, respectively, after an oral dose of 10 mgEq/kg in conscious rats. It also increased plasma ANP immunoreactivity by 103% for up to 4 hours and inhibited the angiotensin I-induced pressor response by an average of 49% within the first 4 hours after the same dosing regimen. By suppressing the biosyntheses of endothelin-1 and angiotensin II, two potent vasoconstrictors, while simultaneously potentiating the circulating levels of ANP, a vasorelaxant and diuretic, CGS 35601 and CGS 37808 may represent novel agents for the treatment of cardiovascular and renal diseases.
authors.affiliation: Cardiovascular Diseases Research, Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07936-1080, USA.
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: Michael E
authors.initials: ME
authors.lastname: Beil
authors.forename: Charles W
authors.initials: CW
authors.lastname: Bruseo
authors.forename: Paula
authors.initials: P
authors.lastname: Savage
authors.forename: Fariborz
authors.initials: F
authors.lastname: Firooznia
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C511403:CGS 35601; C532638:CGS 37808; D004151:Dipeptides; D019332:Endothelin-1; D007211:Indoles; D011355:Prodrugs; D011480:Protease Inhibitors; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes