Synthesis of potent and highly selective inhibitors of human tryptase

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 21; pp. 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: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 04.11.2002; Elsevier
• 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; Allergy; Nitrogen heterocycle; Selectivity; Guinea pig; Structure activity relation; Six membered ring; Piperidine derivatives; Obstructive pulmonary disease; Chemical synthesis; Molecular rigidity; Serine endopeptidases; Four membered ring; Enzyme; Respiratory disease; Rodentia; Enzyme inhibitor; Steric hindrance; Guanidines; Inflammation; In vitro; Asthma; Peptidases; In vivo; Vertebrata; Experimental disease; Mammalia; Animal; Azetidine derivatives; Tryptase; Hydrolases; Piperazine derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00689-3

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. 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.