Angiotensin-converting enzyme inhibitors: synthesis and biological activity of N-substituted tripeptide inhibitors.
A new series of highly potent angiotensin-converting enzyme (ACE) inhibitors, 1-(N2-substituted L-lysyl-gamma-D-glutamyl)octahydro-1H-indole-2-carboxylic acids, was synthesized; various acyl groups were introduced at the alpha-amino group of the N-terminal P1 Lys. The effect of the N2-acyl groups on in vitro inhibitory activity and oral antihypertensive effect was examined. All of the synthesized N-acyl tripeptides were found to have in vitro inhibitory activity at an approximately nanomolar level, and showed antihypertensive potency in renal hypertensive rats at a dose of 10 mg/kg, when administered orally. Among them, compounds 7e, g and 9f, i, m showed potent and long-lasting antihypertensive effects compared with enalapril (2a). Their structure-activity relationships are also discussed.
Sawayama
T
T
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Tsukamoto
M
M
Sasagawa
T
T
Nishimura
K
K
Deguchi
T
T
Takeyama
K
K
Hosoki
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D009842:Oligopeptides; D007703:Peptidyl-Dipeptidase A