title: Synthesis of potent and highly selective inhibitors of human tryptase.
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.
authors.affiliation: The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. william.slusarchyk@bms.com
authors.forename: William A
authors.initials: WA
authors.lastname: Slusarchyk
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: James C
authors.initials: JC
authors.lastname: Sutton
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 / Q000276:immunology; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001388:Aziridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D004355:Drug Stability; D006168:Guinea Pigs; D006801:Humans; 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*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053802:Tryptases
chemical_list: D018927:Anti-Asthmatic Agents; D001384:Azetidines; D001388:Aziridines; C467955:BMS-262084; D010879:Piperazines; D015842:Serine Proteinase Inhibitors; C471993:BMS-363131; D010047:Ovalbumin; D012697:Serine Endopeptidases; D053802:Tryptases