title: Approaches to a multitargeting drug development: first profiled 3- ethoxycarbonyl-1-aza-9-oxafluorenes representing a perspective compound class targeting Alzheimer disease relevant kinases CDK1, CDK5 and GSK-3β.
abstract: Since Alzheimer disease (AD) is a multifactorial disease, recent therapeutical approaches concentrate on the development of a multitargeting drug. Various protein kinases are known to be involved in the progression of AD. A first series of 3-ethoxycarbonyl-1-aza-9-oxafluorenes has been synthesized and biologically evaluated as AD-relevant protein kinase inhibitors. A concentration-dependent inhibition of important AD-relevant kinases has been characterized after the selectivity of kinase inhibition had been demonstrated. Structure-activity relationships of protein kinase inhibition are discussed and first multitargeting inhibitors have been identified.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
authors.forename: Volkmar
authors.initials: V
authors.lastname: Tell
authors.forename: Steffi
authors.initials: S
authors.lastname: Kramer
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.affiliation: Pharmacy, Martin- Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. andreas.hilgeroth@pharmazie.uni-halle.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schachtele
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001681:Biological Assay; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061987:Sf9 Cells; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D005449:Fluorenes; D047428:Protein Kinase Inhibitors; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D016203:CDC2 Protein Kinase; D038362:Glycogen Synthase Kinase 3