Synthesis of potent and selective 2-azepanone inhibitors of human tryptase.
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].
Zhao
Guohua
G
The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. guohua.zhao@bms.com
Bolton
Scott A
SA
Kwon
Chet
C
Hartl
Karen S
KS
Seiler
Steven M
SM
Slusarchyk
William A
WA
Sutton
James C
JC
Bisacchi
Gregory S
GS
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
D001381:Azepines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053802:Tryptases