Abstract
In our search for a new agent, human neutrophil elastase (HNE) inhibitor, for the treatment of acute respiratory failure, we rationally designed and synthesized a series of peptide-based carboxylic acid-containing transition-state inhibitors. The presence of valyl moiety is found to be essential for potent in vitro inhibitory activity and also prevention of an undesirable toxicity. Of these, compound 9m has the most potent in vivo effect on HNE-induced lung hemorrhage in hamsters.
MeSH terms
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Animals
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology
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Cricetinae
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Drug Design
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Hemorrhage / drug therapy
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Humans
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Inhibitory Concentration 50
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Leukocyte Elastase / antagonists & inhibitors*
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Lung Diseases / drug therapy
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Lung Diseases / pathology
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Molecular Mimicry
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Oligopeptides / administration & dosage
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Oligopeptides / chemical synthesis
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Oligopeptides / pharmacology*
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Structure-Activity Relationship
Substances
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Amino Acids
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Carboxylic Acids
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Enzyme Inhibitors
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Oligopeptides
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Leukocyte Elastase