title: The design of potent hydrazones and disulfides as cathepsin S inhibitors.
abstract: The design and synthesis of dipeptidyl disulfides and dipeptidyl benzoylhydrazones as selective inhibitors of the cysteine protease Cathepsin S are described. These inhibitors were expected to form a slowly reversible covalent adduct of the active site cysteine of Cathepsin S. Formation of the initial adduct was confirmed by mass spectral analysis. The nature and mechanism of these adducts was explored. Kinetic analysis of the benzoyl hydrazones indicate that these inhibitors are acting as irreversible inhibitors of Cathepsin S. Additionally, the benzoylhydrazones were shown to be potent inhibitors of Cathepsin S processing of Class II associated invariant peptide both in vitro and in vivo.
authors.affiliation: Department of Medicinal Chemistry, Research and Development Center, Boehringer I Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA. ccywin@rdg.boehringer-ingelheim.com
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Firestone
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McNeil
authors.forename: Christine A
authors.initials: CA
authors.lastname: Grygon
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Crane
authors.forename: Della M
authors.initials: DM
authors.lastname: White
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kinkade
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Hopkins
authors.forename: Walter
authors.initials: W
authors.lastname: Davidson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Labadia
authors.forename: Jessi
authors.initials: J
authors.lastname: Wildeson
authors.forename: Maurice M
authors.initials: MM
authors.lastname: Morelock
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Peterson
authors.forename: Ernest L
authors.initials: EL
authors.lastname: Raymond
authors.forename: Maryanne L
authors.initials: ML
authors.lastname: Brown
authors.forename: Denice M
authors.initials: DM
authors.lastname: Spero
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004220:Disulfides / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011233:Precipitin Tests; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004220:Disulfides; D006835:Hydrazones; D011994:Recombinant Proteins; D002403:Cathepsins; D010196:Pancreatic Elastase; D002401:Cathepsin B; C028217:cathepsin S