title: Synthesis of potent and selective 2-azepanone inhibitors of human tryptase.
abstract: The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].
authors.affiliation: The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. guohua.zhao@bms.com
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Scott A
authors.initials: SA
authors.lastname: Bolton
authors.forename: Chet
authors.initials: C
authors.lastname: Kwon
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hartl
authors.forename: Steven M
authors.initials: SM
authors.lastname: Seiler
authors.forename: William A
authors.initials: WA
authors.lastname: Slusarchyk
authors.forename: James C
authors.initials: JC
authors.lastname: Sutton
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Bisacchi
mesh_terms: D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D053802:Tryptases
chemical_list: D001381:Azepines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053802:Tryptases