Abstract
A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.
MeSH terms
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Administration, Oral
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Animals
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Azetidines / chemistry
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Binding Sites
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Cricetinae
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Crystallography, X-Ray
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Drug Design*
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Fluorocarbons / chemistry
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Fluorocarbons / metabolism
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Fluorocarbons / pharmacology
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Hemorrhage / chemically induced
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Hemorrhage / enzymology
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Hemorrhage / prevention & control
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Humans
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Isoquinolines / chemistry
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Ketones* / chemical synthesis
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Ketones* / chemistry
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Ketones* / metabolism
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Ketones* / pharmacology
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Leukocyte Elastase / antagonists & inhibitors*
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Leukocyte Elastase / metabolism
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Lung Diseases / chemically induced
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Lung Diseases / enzymology
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Lung Diseases / prevention & control
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Models, Molecular
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Molecular Conformation
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Neutrophils / enzymology*
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Oligopeptides* / chemical synthesis
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Oligopeptides* / chemistry
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Oligopeptides* / metabolism
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Oligopeptides* / pharmacology
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Pancreatic Elastase / antagonists & inhibitors
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Pancreatic Elastase / metabolism
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Proline / analogs & derivatives
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Proline / chemistry
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Serine Proteinase Inhibitors* / chemical synthesis
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Serine Proteinase Inhibitors* / chemistry
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Serine Proteinase Inhibitors* / metabolism
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Serine Proteinase Inhibitors* / pharmacology
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Structure-Activity Relationship
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Swine
Substances
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Azetidines
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Fluorocarbons
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Isoquinolines
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Ketones
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Oligopeptides
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Serine Proteinase Inhibitors
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azetidine
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Proline
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homoproline
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Pancreatic Elastase
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Leukocyte Elastase
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isoquinoline