Synthesis and angiotensin-converting enzyme inhibitory activity of 3-(Mercaptomethyl)-2-oxo-1-pyrrolidineacetic acids and 3-(Mercaptomethyl)-2-oxo-1-piperidineacetic acids.

Abstract

A number of gamma- and delta-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared. The structures of these compounds were designed to include many of the important features of captopril. The synthesis involved the preparation of a variety of novel 3-methylene-2-pyrrolidinones (3-5 and 16) and 3-methylene-2-piperidinones (3a-5a, 10-12, and 17). The key intermediate 3-methylenelactams 3 and 3a were obtained from 3-(hydroxymethyl)lactams 2 and 2a by a direct dehydration with dicyclohexylcarbodiimide using cuprous iodide as a catalyst. Introduction of the sulfhydryl group was accomplished by a Michael addition of these alpha, beta-unsaturated lactams. The compound with the highest in vitro activity was 3-(mercaptomethyl)-2-oxo-1-piperidineacetic acid (7a). The activity of the 7a both in vitro and in vivo (dog) was shown to be less than that of captopril by a factor of about 100.

• Authors: S Klutchko, M L Hoefle, R D Smith, A D Essenburg, R B Parker, V L Nemeth, M J Ryan, D H Dugan, H R Kaplan
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 24 Issue 1 Pg. 104-9 (Jan 1981) ISSN: 0022-2623 [Print] United States
• PMID: 6259352 (Publication Type: Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Pyrrolidinones
• Captopril
• Pyrrolidonecarboxylic Acid

Topics

• Angiotensin-Converting Enzyme Inhibitors
• Animals
• Captopril (pharmacology)
• Chemical Phenomena
• Chemistry
• Dogs
• Guinea Pigs
• Hemodynamics (drug effects)
• In Vitro Techniques
• Muscle Contraction (drug effects)
• Pyrrolidinones (chemical synthesis)
• Pyrrolidonecarboxylic Acid (analogs & derivatives, chemical synthesis, pharmacology)