Inhibition of human leukocyte elastase. 4. Selection of a substituted cephalosporin (L-658,758) as a topical aerosol

Human leukocyte elastase (HLE) is a serine protease which has been implicated as a causative agent in several pulmonary diseases. The continued modification of our previously reported cephalosporin-based HLE inhibitors has led to the identification of a series of C-2 amides with potent, topical acti...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-10, Vol.35 (21), p.3731-3744
Main Authors: Finke, Paul E, Shah, Shrenik K, Ashe, Bonnie M, Ball, Richard G, Blacklock, Thomas J, Bonney, Robert J, Brause, Karen A, Chandler, Gilbert O, Cotton, Meredith
Format: Article
Language:English
Subjects:
Administration, Topical
Aerosols
Animals
cephalosporin
Cephalosporins
Chemistry
Cricetinae
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Humans
inhibition
Leukocyte Elastase
man
Molecular Structure
Organic chemistry
Pancreatic Elastase - antagonists & inhibitors
Preparations and properties
Pyrrolidines - administration & dosage
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Rats
X-Ray Diffraction
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Summary:Human leukocyte elastase (HLE) is a serine protease which has been implicated as a causative agent in several pulmonary diseases. The continued modification of our previously reported cephalosporin-based HLE inhibitors has led to the identification of a series of C-2 amides with potent, topical activity in an in vivo hamster lung hemorrhage model. While the most potent in vitro HLE inhibition had previously been obtained with lipophilic ester derivatives, it was found that the less active, but more polar and stable, amide derivatives were much more effective in vivo. The development of the structure--activity relations for optimization of these activities is discussed. These results led to the selection of 3-(acetoxymethyl)-2-[(2(S)-carboxypyrrolidino)carbonyl]-7 alpha-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, 5,5-dioxide (3, L-658,758) as a selective, potent, time-dependent HLE inhibitor suitable for formulation as a topical aerosol drug for possible clinical use.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00099a002