Synthesis and pharmacological activity of angiotensin-converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines

• Published in: Journal of medicinal chemistry 1988-04, Vol.31 (4), p.875-885
• Main Authors: Smith, Elizabeth M, Swiss, Gerald F, Neustadt, Bernard R, Gold, Elijah H, Sommer, Jane A, Brown, Arthur D, Chiu, Peter J. S, Moran, Rosa, Sybertz, Edmund J, Baum, Thomas
• Format: Article
• Language: English
• Subjects: Angiotensin-Converting Enzyme Inhibitors - chemical synthesis; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - therapeutic use; Bradykinin - metabolism; Chemistry; dipeptidyl carboxypeptidase I inhibitor; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hypertension - drug therapy; Hypertension - enzymology; Organic chemistry; Peptidyl-Dipeptidase A - metabolism; Preparations and properties; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - pharmacology; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00399a033

The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.