Inhibition of Human Neutrophil Elastase. 3. An Orally Active Enol Acetate Prodrug

Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[3,3,4,4,4-penta fluoro-1- (1-methylethyl)-2-oxobutyl]-L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE). Observations mad...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-01, Vol.38 (2), p.223-233
Main Authors: Burkhart, Joseph P, Koehl, Jack R, Mehdi, Shujaath, Durham, Sherrie L, Janusz, Michael J, Huber, Edward W, Angelastro, Michael R, Sunder, Shyam, Metz, William A
Format: Article
Language:English
Subjects:
Acetates
Animals
Cricetinae
Humans
Ketones
Leukocyte Elastase - antagonists & inhibitors
Magnetic Resonance Spectroscopy
Neutrophils - enzymology
Pancreatic Elastase - antagonists & inhibitors
Prodrugs - chemistry
Protease Inhibitors - administration & dosage
Stereoisomerism
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Summary:Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[3,3,4,4,4-penta fluoro-1- (1-methylethyl)-2-oxobutyl]-L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE). Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P1. In vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo. The ED50 value for (E)-N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2- (acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-buteny l]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00002a003