title: Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors.
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.
authors.affiliation: The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. james.sutton@bms.com
authors.forename: James C
authors.initials: JC
authors.lastname: Sutton
authors.forename: Scott A
authors.initials: SA
authors.lastname: Bolton
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hartl
authors.forename: Ming-Hsing
authors.initials: MH
authors.lastname: Huang
authors.forename: Glenn
authors.initials: G
authors.lastname: Jacobs
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Martin L
authors.initials: ML
authors.lastname: Ogletree
authors.forename: Zulan
authors.initials: Z
authors.lastname: Pi
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Steven M
authors.initials: SM
authors.lastname: Seiler
authors.forename: William A
authors.initials: WA
authors.lastname: Slusarchyk
authors.forename: Uwe
authors.initials: U
authors.lastname: Treuner
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Bisacchi
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000473:pathology; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D018360:Crystallography, X-Ray; D005110:Extracellular Space / Q000187:drug effects; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000473:pathology; D008968:Molecular Conformation; D010047:Ovalbumin / Q000276:immunology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053802:Tryptases
chemical_list: D018927:Anti-Asthmatic Agents; D001384:Azetidines; C467955:BMS-262084; D010879:Piperazines; D015842:Serine Proteinase Inhibitors; D010047:Ovalbumin; D012697:Serine Endopeptidases; D053802:Tryptases