title: Synthesis of potent and highly selective nonguanidine azetidinone inhibitors of human tryptase.
abstract: 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.
authors.affiliation: The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. gregory.bisacchi@bms.com
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Bisacchi
authors.forename: William A
authors.initials: WA
authors.lastname: Slusarchyk
authors.forename: Scott A
authors.initials: SA
authors.lastname: Bolton
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hartl
authors.forename: Glenn
authors.initials: G
authors.lastname: Jacobs
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Martin L
authors.initials: ML
authors.lastname: Ogletree
authors.forename: Zulan
authors.initials: Z
authors.lastname: Pi
authors.forename: James C
authors.initials: JC
authors.lastname: Sutton
authors.forename: Uwe
authors.initials: U
authors.lastname: Treuner
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Steven M
authors.initials: SM
authors.lastname: Seiler
mesh_terms: 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
chemical_list: D001384:Azetidines; D015842:Serine Proteinase Inhibitors; C082735:azetidine; D012697:Serine Endopeptidases; D053802:Tryptases