Abstract
A new series of benzoxazinone analogs were designed, synthesized, and assayed to determine their effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils. Of these, compounds 6-10 showed a potent dual inhibitory effect on NE release and superoxide anion generation. In contrast, compounds 11-15 exhibited highly selective and potent inhibitory activities on NE release. These results indicate that the inhibitory activity on NE release in FMLP-activated human neutrophils depended on the position of chloro-substituent in the A ring. On the other hand, 13 significantly attenuated the increase in myeloperoxidase (MPO) activity and edema in the lung of rats after trauma-hemorrhagic shock. Therefore, these compounds could be developed as new NE inhibitors.
Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use
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Benzoxazines / chemical synthesis*
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Benzoxazines / chemistry
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Benzoxazines / pharmacology*
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Benzoxazines / therapeutic use
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Drug Design
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Humans
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Inhibitory Concentration 50
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Leukocyte Elastase / antagonists & inhibitors*
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Leukocytes / enzymology
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Lung Injury / drug therapy*
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Lung Injury / etiology*
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Male
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Proteinase Inhibitory Proteins, Secretory / chemical synthesis
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Proteinase Inhibitory Proteins, Secretory / chemistry
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Proteinase Inhibitory Proteins, Secretory / pharmacology
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Proteinase Inhibitory Proteins, Secretory / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Shock, Hemorrhagic / complications*
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Young Adult
Substances
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Anti-Inflammatory Agents
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Benzoxazines
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Proteinase Inhibitory Proteins, Secretory
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Leukocyte Elastase