3,4-disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P3 elements for potency and selectivity.
The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K.
Setti
Eduardo L
EL
Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. eduardo.setti@celera.com
Davis
Dana
D
Janc
James W
JW
Jeffery
Douglas A
DA
Cheung
Harry
H
Yu
Walter
W
D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007700:Kinetics; D015394:Molecular Structure; D013329:Structure-Activity Relationship
C116379:2-azetidinone; D001384:Azetidines; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K