Abstract
The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.
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 / immunology
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Azetidines / chemical synthesis*
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Azetidines / pharmacology*
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Aziridines / chemical synthesis*
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Aziridines / pharmacology*
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Drug Stability
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Guinea Pigs
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Humans
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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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Stereoisomerism
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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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Aziridines
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BMS-262084
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Piperazines
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Serine Proteinase Inhibitors
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BMS-363131
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Ovalbumin
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Serine Endopeptidases
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Tryptases