title: Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
abstract: 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.
authors.affiliation: Department of Research Bioanalysis and Drug Metabolism, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Kim K
authors.initials: KK
authors.lastname: Adkison
authors.forename: David G
authors.initials: DG
authors.lastname: Barrett
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Robert T
authors.initials: RT
authors.lastname: Gampe
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Stacey T
authors.initials: ST
authors.lastname: Long
authors.forename: Robert B
authors.initials: RB
authors.lastname: McFadyen
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Larry R
authors.initials: LR
authors.lastname: Miller
authors.forename: J Alan
authors.initials: JA
authors.lastname: Payne
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Derril H
authors.initials: DH
authors.lastname: Willard
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
mesh_terms: 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
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D011355:Prodrugs; D012664:Semicarbazones; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat