Heterocyclic lactam derivatives as dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibitors.
A series of 13- and 14-membered ring lactam derivatives 9a,b, 10, 11, and 12a-c was prepared from L-cysteine. Compounds 9a,b and 12a,b were tested in vitro for inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition. The structure-activity profile of the series is discussed. Compound 9b, a 13-membered ring macrocyclic lactam, had an NEP IC50 of 18 nM and an ACEIC50 of 12 nM in vitro and showed dual plasma inhibition after intravenous or oral administration.
Stanton
J L
JL
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Sperbeck
D M
DM
Trapani
A J
AJ
Cote
D
D
Sakane
Y
Y
Berry
C J
CJ
Ghai
R D
RD
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D010456:Peptides, Cyclic; C084670:6-(mercaptomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid; D015260:Neprilysin; D003545:Cysteine