Synthesis of potent and highly selective inhibitors of human tryptase

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 503000...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2002-11, Vol.12 (21), p.3235-3238
Main Authors: Slusarchyk, William A., Bolton, Scott A., Hartl, Karen S., Huang, Ming-Hsing, Jacobs, Glenn, Meng, Wei, Ogletree, Martin L., Pi, Zulan, Schumacher, William A., Seiler, Steven M., Sutton, James C., Treuner, Uwe, Zahler, Robert, Zhao, Guohua, Bisacchi, Gregory S.
Format: Article
Language:English
Subjects:
Allergic diseases
Animals
Anti-Asthmatic Agents - chemical synthesis
Anti-Asthmatic Agents - pharmacology
Asthma - drug therapy
Asthma - immunology
Azetidines - chemical synthesis
Azetidines - pharmacology
Aziridines - chemical synthesis
Aziridines - pharmacology
Biological and medical sciences
Drug Stability
Guinea Pigs
Humans
Immunopathology
Medical sciences
Ovalbumin - immunology
Pharmacology. Drug treatments
Piperazines - chemical synthesis
Piperazines - pharmacology
Respiratory and ent allergic diseases
Respiratory system
Serine Endopeptidases - metabolism
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - pharmacology
Stereoisomerism
Structure-Activity Relationship
Tryptases
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Summary: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 503000-fold) for tryptase versus related serine proteases including trypsin. The synthesis and SAR of a series of azetidinones are described resulting in identification of BMS-363131 as a potent inhibitor of human tryptase with high selectivity for tryptase versus related serine proteases including trypsin.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(02)00689-3