Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?

Article Details

Citation

Copy to clipboard

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