title: Angiotensin converting enzyme inhibitors: modifications of a tripeptide analogue.
abstract: Modified nonhydrolyzable tripeptide analogues of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1), designed to impart oral angiotensin converting enzyme (ACE) inhibitory activity, were made and evaluated in vivo and in vitro. The N-methyl and C5-methyl analogues of 1 were inactive. Insertion of heteroatoms (O, S, NH) into the C--C chain of 1 gave a series of compounds with high in vitro activity in the guinea pig serum ACE assay. The O-analogue was the most potent with an IC50 = 4.4 x 10(-9) M compared to 1 with an IC50 = 3.2 x 10(-9) M. The structure-activity relationships in this series of compounds lead one to speculate that the heteroatom provides an additional binding site to the surface of the enzyme; however, these compounds were inactive when tested for antihypertensive activity in the renal hypertensive rat at 30 mg/kg by the oral route (captopril is active at 1.0 mg/kg po).
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006977:Hypertension, Renal / Q000201:enzymology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides