Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Adkison
Kim K
KK
Department of Research Bioanalysis and Drug Metabolism, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Barrett
David G
DG
Deaton
David N
DN
Gampe
Robert T
RT
Hassell
Anne M
AM
Long
Stacey T
ST
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Payne
J Alan
JA
Shewchuk
Lisa M
LM
Wells-Knecht
Kevin J
KJ
Willard
Derril H
DH
Wright
Lois L
LL
D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012664:Semicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
D000447:Aldehydes; D004791:Enzyme Inhibitors; D011355:Prodrugs; D012664:Semicarbazones; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat