title: Probing novel 1-aza-9-oxafluorenes as selective GSK-3beta inhibitors.
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.affiliation: Institute of Pharmacy, Martin-Luther University, Halle, Germany, Fax: +49 345 5527026.
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Voigt
authors.forename: Martin
authors.initials: M
authors.lastname: Krug
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000577:Amides / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005449:Fluorenes / Q000138:chemical synthesis / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D018411:Spodoptera; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D005449:Fluorenes; D016875:tau Proteins; D000255:Adenosine Triphosphate; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3