Abstract
We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.
MeSH terms
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Benzhydryl Compounds / chemical synthesis*
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Benzhydryl Compounds / chemistry
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Benzhydryl Compounds / pharmacology
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Binding Sites
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Binding, Competitive
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Blood Proteins / metabolism
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Blood Proteins / pharmacology
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Cathepsin G
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Cathepsins / antagonists & inhibitors
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Kinetics
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Leukocyte Elastase / antagonists & inhibitors*
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Molecular Structure
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Oligopeptides / pharmacology
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Phenoxyacetates / chemical synthesis*
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Phenoxyacetates / chemistry
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Phenoxyacetates / pharmacology
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Pyrrolidonecarboxylic Acid / analogs & derivatives
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Serine Endopeptidases
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Thrombin / antagonists & inhibitors
Substances
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Benzhydryl Compounds
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Blood Proteins
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Enzyme Inhibitors
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Oligopeptides
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Phenoxyacetates
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S 2484
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Cathepsins
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Serine Endopeptidases
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CTSG protein, human
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Cathepsin G
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Leukocyte Elastase
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Thrombin
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Pyrrolidonecarboxylic Acid