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

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, Wright LL
Bioorg Med Chem Lett 16 978-83 (2006)
Cited: 7 times
EuropePMC logo PMID: 16290936

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.

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Reviews citing this publication (1)

  1. Biochemical properties and regulation of cathepsin K activity. Lecaille F, Brömme D, Lalmanach G. Biochimie 90 208-226 (2008)

Articles citing this publication (4)

  1. Molecular dynamics simulations of the catalytic pathway of a cysteine protease: a combined QM/MM study of human cathepsin K. Ma S, Devi-Kesavan LS, Gao J. J Am Chem Soc 129 13633-13645 (2007)
  2. Proteasome inhibition by peptide-semicarbazones. Leban J, Blisse M, Krauss B, Rath S, Baumgartner R, Seifert MH. Bioorg Med Chem 16 4579-4588 (2008)
  3. Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling. Yuan XY, Fu DY, Ren XF, Fang X, Wang L, Zou S, Wu Y. Org Biomol Chem 11 5847-5852 (2013)
  4. Structure-Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry. Jung ME, Chamberlain BT, Ho CL, Gillespie EJ, Bradley KA. ACS Med Chem Lett 5 363-367 (2014)


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