Synthesis and angiotensin converting enzyme inhibitory activity of N-carboxymethyldipeptides with omega-(4-piperidyl)alkyl group.
The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing 1(S)-carboxy-omega-(4-piperidyl)alkyl group at the N-terminal of the dipeptide is described. These 1-carboxy-omega-(4-piperidyl)alkyl derivatives possess greater or equivalent in vitro potency and in vivo efficacy than captopril and enalapril. The length (n) of the carbon chain in the omega-(4-piperidyl)alkyl moiety was varied from two to six to investigate the optimal structure for long-acting ACE inhibitors. 1-[N-[1(S)-Carboxy-6-(4- piperidyl)hexyl]-L-alanyl]-(2a,3a beta, 7a beta)-octahydro- 1H-indole-2-carboxylic acid (9b), the most potent member of the series, had an in vivo area under the curve (AUC) of 685, which was calculated by the inhibition of angiotensin I-induced pressor response vs. time curves (0 to 8 h) after p.o. administration.
Waga
T
T
Central Research Laboratories, Asahi Breweries, Ltd., Tokyo, Japan.
Matsui
S
S
Saito
S
S
Watanabe
M
M
Kajiwara
Y
Y
Shirota
M
M
Iijima
M
M
Kitabatake
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004656:Enalapril / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D015773:Enalaprilat / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011921:Rats, Inbred WKY
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D010880:Piperidines; D004656:Enalapril; D002216:Captopril; D015773:Enalaprilat