Bioorganic & medicinal chemistry letters, 2006-02, Vol.16 (4), p.978-983
2006
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Details
- Autor(en) / Beteiligte
- Titel
- Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
- Ist Teil von
- Bioorganic & medicinal chemistry letters, 2006-02, Vol.16 (4), p.978-983
- Ort / Verlag
- Oxford: Elsevier Ltd
- Erscheinungsjahr
- 2006
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-894XeISSN: 1464-3405DOI: 10.1016/j.bmcl.2005.10.108Titel-ID: cdi_proquest_miscellaneous_67615614
- Format
- –
- Schlagworte
- Aldehydes, Aldehydes - chemistry, Animals, Biological and medical sciences, Bones, joints and connective tissue. Antiinflammatory agents, Cathepsin K, Cathepsin K inhibitors, Cathepsins - antagonists & inhibitors, Crystallography, X-Ray, Cysteine protease inhibitors, Drug Evaluation, Preclinical, Enzyme Inhibitors - chemical synthesis, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Humans, Hydrogen-Ion Concentration, Hydrolysis, Medical sciences, Models, Molecular, Molecular Conformation, Pharmacology. Drug treatments, Prodrugs, Prodrugs - chemical synthesis, Prodrugs - chemistry, Prodrugs - pharmacology, Rats, Semicarbazones, Semicarbazones - chemical synthesis, Semicarbazones - chemistry, Semicarbazones - pharmacology, Solubility, Structure-Activity Relationship