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.