Angiotensin-converting enzyme inhibitors: synthesis and biological activity of N-substituted tripeptide inhibitors

• Published in: Chemical & pharmaceutical bulletin Vol. 38; no. 1; pp. 110 - 115
• Main Authors: SAWAYAMA, T, TSUKAMOTO, M, SASAGAWA, T, NISHIMURA, K, DEGUCHI, T, TAKEYAMA, K, HOSOKI, K
• Format: Journal Article
• Language: English
• Published: Tokyo Maruzen 1990
• Subjects: Angiotensin-Converting Enzyme Inhibitors - chemical synthesis; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Blood Pressure - drug effects; Chemical Phenomena; Chemistry; Exact sciences and technology; Indoles - chemical synthesis; Indoles - pharmacology; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Organic chemistry; Peptides; Peptidyl-Dipeptidase A - metabolism; Preparations and properties; Rats; Structure activity relation; Nitrogen heterocycle; Angiotensin converting enzyme; Tripeptide; Bicyclic compound; Enzyme inhibitor; Antihypertensive agent; Liquid phase; In vitro; Biological activity
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.38.110

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.