title: 3,4-disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P3 elements for potency and selectivity.
abstract: 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.
authors.affiliation: Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. eduardo.setti@celera.com
authors.forename: Eduardo L
authors.initials: EL
authors.lastname: Setti
authors.forename: Dana
authors.initials: D
authors.lastname: Davis
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Jeffery
authors.forename: Harry
authors.initials: H
authors.lastname: Cheung
authors.forename: Walter
authors.initials: W
authors.lastname: Yu
mesh_terms: 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
chemical_list: C116379:2-azetidinone; D001384:Azetidines; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K