The design of potent hydrazones and disulfides as cathepsin S inhibitors.
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.
Cywin
Charles L
CL
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
Firestone
Raymond A
RA
McNeil
Daniel W
DW
Grygon
Christine A
CA
Crane
Kathryn M
KM
White
Della M
DM
Kinkade
Peter R
PR
Hopkins
Jerry L
JL
Davidson
Walter
W
Labadia
Mark E
ME
Wildeson
Jessi
J
Morelock
Maurice M
MM
Peterson
Jeffrey D
JD
Raymond
Ernest L
EL
Brown
Maryanne L
ML
Spero
Denice M
DM
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
D015853:Cysteine Proteinase Inhibitors; D004220:Disulfides; D006835:Hydrazones; D011994:Recombinant Proteins; D002403:Cathepsins; D010196:Pancreatic Elastase; D002401:Cathepsin B; C028217:cathepsin S