Orally active .beta.-lactam inhibitors of human leukocyte elastase-1. Activity of 3,3-diethyl-2-azetidinones

• Published in: Journal of medicinal chemistry Vol. 35; no. 21; pp. 3745 - 3754
• Main Authors: Shah, Shrenik K, Dorn, Conrad P, Finke, Paul E, Hale, Jeffrey J, Hagmann, William K, Brause, Karen A, Chandler, Gilbert O, Kissinger, Amy L, Ashe, Bonnie M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-10-1992
• Subjects: 3,3-diethyl-2-azetidinone; activity; Administration, Oral; Amino Acid Sequence; Animals; Azetidines - administration & dosage; Azetidines - chemistry; Azetidines - pharmacology; beta -lactams; beta-Lactams - administration & dosage; beta-Lactams - pharmacology; Chemistry; Cricetinae; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Hydrolysis; inhibition; Leukocyte Elastase; Magnetic Resonance Spectroscopy; man; Molecular Sequence Data; Organic chemistry; Pancreatic Elastase - antagonists & inhibitors; Preparations and properties; X-Ray Diffraction; Four membered ring; Enzyme; Nitrogen heterocycle; Proteinase; Lactam; Oral administration; Enzyme inhibitor; In vitro; Biological activity; In vivo; Structure activity relation; Carboxylic acid; Ureas
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00099a003

A thorough analysis of the mechanism of inhibition of human leukocyte elastase (HLE) by a monocyclic beta-lactam and the mechanism of beta-lactam hydrolysis led to the preparation of potent and highly stable inhibitors of HLE. This work led to the identification of 4-[(4-carboxyphenyl)-oxy]-3,3-diethyl-1- [[(phenylmethyl)amino]carbonyl]-2-azetidinone (2) as the first orally active inhibitor of human leukocyte elastase (HLE). Analogs of 2 with different substituents on the urea N were synthesized and evaluated for their activity in vitro against HLE as well as in vivo in a hamster lung hemorrhage model. Compounds with a methyl or a methoxy group in the para position of the benzene ring were very potent in both assays. The results are discussed on the basis of the proposed model for the binding of this class of inhibitors to HLE and a possible mechanism of inhibition is presented.