Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9-oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases
作者： Volkmar Tell , Max Holzer , Lydia Herrmann , Kazem Ahmed Mahmoud , Christoph Schächtele
DOI: 10.1016/J.BMCL.2012.09.006
关键词: Stereochemistry 、 Cyclin-dependent kinase 1 、 GSK-3 、 Cancer research 、 Tau protein 、 Chemistry 、 Protein kinase inhibitor 、 CDC2 Protein Kinase 、 Protein kinase A 、 Cyclin-dependent kinase 5 、 Drug development
摘要: Alzheimer disease (AD) turned out to be a multifactorial process leading neuronal decay. So far merely single target structures which attribute the AD progression have been considered develop specific drugs. However, such drug developments disappointing in clinical stages. Multitargeting of more than one structure determines recent studies developing novel lead compounds. Protein kinases identified contribute decay with CDK1, GSK-3β and CDK5/p25 being involved pathological tau protein hyperphosphorylation. We discovered dihydroxy-1-aza-9-oxafluorene type nanomolar activities against CDK5/p25. Structure-activity relationships (SAR) kinase inhibition are discussed within our first compound series. One active profiled as selective inhibitor. Bioanalysis harmless cellular toxicity phosphorylation qualifies for further studies.
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