Abstract
A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.
MeSH terms
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Animals
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Anti-Asthmatic Agents / chemical synthesis*
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Anti-Asthmatic Agents / pharmacology*
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Asthma / drug therapy
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Asthma / pathology
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Azetidines / chemical synthesis*
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Azetidines / pharmacology*
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Bronchoconstriction / drug effects
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Crystallography, X-Ray
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Extracellular Space / drug effects
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Guinea Pigs
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Half-Life
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Humans
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Inflammation / pathology
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Lung / pathology
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Molecular Conformation
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Ovalbumin / immunology
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Piperazines / chemical synthesis*
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Piperazines / pharmacology*
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Serine Endopeptidases / metabolism*
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tryptases
Substances
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Anti-Asthmatic Agents
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Azetidines
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BMS-262084
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Piperazines
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Serine Proteinase Inhibitors
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Ovalbumin
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Serine Endopeptidases
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Tryptases