Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
Article Details
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Adkison KK, Barrett DG, Deaton DN, Gampe RT, Hassell AM, Long ST, McFadyen RB, Miller AB, Miller LR, Payne JA, Shewchuk LM, Wells-Knecht KJ, Willard DH Jr, Wright LL
Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
Bioorg Med Chem Lett. 2006 Feb 15;16(4):978-83. Epub 2005 Nov 15.
- PubMed ID
- 16290936 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) (2R)-3-Methyl-1-phenyl-2-butanyl [(2S)-1-oxo-2-hexanyl]carbamate Cathepsin K IC 50 (nM) 0.5 N/A N/A Details 1-(PHENYLMETHYL)CYCLOPENTYL[(1S)-1-FORMYLPENTYL]CARBAMATE Cathepsin K IC 50 (nM) 0.35 N/A N/A Details