Synthesis of potent and highly selective nonguanidine azetidinone inhibitors of human tryptase.
Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.
Bisacchi
Gregory S
GS
The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. gregory.bisacchi@bms.com
Slusarchyk
William A
WA
Bolton
Scott A
SA
Hartl
Karen S
KS
Jacobs
Glenn
G
Mathur
Arvind
A
Meng
Wei
W
Ogletree
Martin L
ML
Pi
Zulan
Z
Sutton
James C
JC
Treuner
Uwe
U
Zahler
Robert
R
Zhao
Guohua
G
Seiler
Steven M
SM
D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053802:Tryptases
D001384:Azetidines; D015842:Serine Proteinase Inhibitors; C082735:azetidine; D012697:Serine Endopeptidases; D053802:Tryptases