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.