New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.
Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
Fink
C A
CA
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901, USA.
Qiao
Y
Y
Berry
C J
CJ
Sakane
Y
Y
Ghai
R D
RD
Trapani
A J
AJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; C097596:N-((1-((2-acetylmercapto-3-methyl-1-oxobutyl)amino)-1-cyclopentyl)carbonyl)tryptophan ethyl ester; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; C049331:racecadotril; D009320:Atrial Natriuretic Factor; D014364:Tryptophan; D002216:Captopril; D015244:Thiorphan; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin