Synthesis of potent and highly selective inhibitors of human tryptase.
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.
Slusarchyk
William A
WA
The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. william.slusarchyk@bms.com
Bolton
Scott A
SA
Hartl
Karen S
KS
Huang
Ming-Hsing
MH
Jacobs
Glenn
G
Meng
Wei
W
Ogletree
Martin L
ML
Pi
Zulan
Z
Schumacher
William A
WA
Seiler
Steven M
SM
Sutton
James C
JC
Treuner
Uwe
U
Zahler
Robert
R
Zhao
Guohua
G
Bisacchi
Gregory S
GS
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
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