Angiotensin converting enzyme inhibitors: modifications of a tripeptide analog

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Abstract
Modified nonhydrolyzable tripeptide analogs 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 analogs 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-analog was the most potent, with an IC50 [median inhibitory concentration] = 4.4 .times. 10-9 M compared to 1 with an IC50 = 3.2 .times. 10-9 M. The structure-activity relationships in this series of compounds may indicate that the heteroatom provides an additional binding site to the surface of the enzyme; 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 [orally]).