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Probing novel 1-aza-9-oxafluorenes as selective GSK-3beta inhibitors.
ChemMedChem. 2008 Jan; 3(1):120-6.C

Abstract

Within the histopathology of Alzheimer's disease (AD) certain hallmarks are beeing observed. The occurance of protein deposits belong to such characteristic features. Such deposits can be found extracellular as beta-amyloid (Abeta) plaques and intracellular as neurofibrillary tangles (NFTs). In the search for novel AD therapeutics it became of great interest to investigate the formation of NFTs and their contribution to the AD symptomatic. NFTs consist of hyperphosphorylated tau protein. Within the phosphorylation process of tau protein two kinases are of great importance: cyclin dependent kinase 5 (cdk5) and its truncated regulatory subunit p25 and glycogen synthase kinase 3beta (GSK-3beta). The role of both kinases within the NFT formation process is still under debate. To better understand the pathophysiological process highly selective inhibitors of both kinases are of value. Known inhibitors lack the necessary selectivity. We developed novel 1-aza-9-oxafluo-renes as selective GSK-3beta inhibitors. Structure-activity relationships of a series of 4-phenyl substituted derivatives are discussed. Variation of the 3-side chain led to selective carbonyl amide derivatives with selectivity factors of more than 100 at the tested ATP competitor concentrations. Such selectivities permit specific investigation of the role of GSK-3beta within the NFT formation processes.

Authors+Show Affiliations

Voigt B
Institute of Pharmacy, Martin-Luther University, Halle, Germany, Fax: +49 345 5527026.
Krug M
No affiliation info available
Schächtele C
No affiliation info available
Totzke F
No affiliation info available
Hilgeroth A
No affiliation info available

MeSH

Adenosine TriphosphateAlzheimer DiseaseAmidesAmyloid beta-PeptidesAnimalsAza CompoundsBinding SitesCell LineCyclin-Dependent Kinase 5Enzyme InhibitorsFluorenesGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHumansNeurofibrillary TanglesPhosphorylationSpodopteraStructure-Activity Relationshiptau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18000938

Citation

Voigt, Burkhardt, et al. "Probing Novel 1-aza-9-oxafluorenes as Selective GSK-3beta Inhibitors." ChemMedChem, vol. 3, no. 1, 2008, pp. 120-6.
Voigt B, Krug M, Schächtele C, et al. Probing novel 1-aza-9-oxafluorenes as selective GSK-3beta inhibitors. ChemMedChem. 2008;3(1):120-6.
Voigt, B., Krug, M., Schächtele, C., Totzke, F., & Hilgeroth, A. (2008). Probing novel 1-aza-9-oxafluorenes as selective GSK-3beta inhibitors. ChemMedChem, 3(1), 120-6.
Voigt B, et al. Probing Novel 1-aza-9-oxafluorenes as Selective GSK-3beta Inhibitors. ChemMedChem. 2008;3(1):120-6. PubMed PMID: 18000938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Probing novel 1-aza-9-oxafluorenes as selective GSK-3beta inhibitors. AU - Voigt,Burkhardt, AU - Krug,Martin, AU - Schächtele,Christoph, AU - Totzke,Frank, AU - Hilgeroth,Andreas, PY - 2007/11/15/pubmed PY - 2008/7/31/medline PY - 2007/11/15/entrez SP - 120 EP - 6 JF - ChemMedChem JO - ChemMedChem VL - 3 IS - 1 N2 - Within the histopathology of Alzheimer's disease (AD) certain hallmarks are beeing observed. The occurance of protein deposits belong to such characteristic features. Such deposits can be found extracellular as beta-amyloid (Abeta) plaques and intracellular as neurofibrillary tangles (NFTs). In the search for novel AD therapeutics it became of great interest to investigate the formation of NFTs and their contribution to the AD symptomatic. NFTs consist of hyperphosphorylated tau protein. Within the phosphorylation process of tau protein two kinases are of great importance: cyclin dependent kinase 5 (cdk5) and its truncated regulatory subunit p25 and glycogen synthase kinase 3beta (GSK-3beta). The role of both kinases within the NFT formation process is still under debate. To better understand the pathophysiological process highly selective inhibitors of both kinases are of value. Known inhibitors lack the necessary selectivity. We developed novel 1-aza-9-oxafluo-renes as selective GSK-3beta inhibitors. Structure-activity relationships of a series of 4-phenyl substituted derivatives are discussed. Variation of the 3-side chain led to selective carbonyl amide derivatives with selectivity factors of more than 100 at the tested ATP competitor concentrations. Such selectivities permit specific investigation of the role of GSK-3beta within the NFT formation processes. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/18000938/Probing_novel_1_aza_9_oxafluorenes_as_selective_GSK_3beta_inhibitors_ DB - PRIME DP - Unbound Medicine ER -
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