Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors.
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.
Sutton
James C
JC
The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. james.sutton@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
Slusarchyk
William A
WA
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 / 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
D018927:Anti-Asthmatic Agents; D001384:Azetidines; C467955:BMS-262084; D010879:Piperazines; D015842:Serine Proteinase Inhibitors; D010047:Ovalbumin; D012697:Serine Endopeptidases; D053802:Tryptases