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.
Subject(s)
Alzheimer Disease/enzymology , CDC2 Protein Kinase/metabolism , Cyclin-Dependent Kinase 5/metabolism , Drug Design , Fluorenes/chemistry , Fluorenes/pharmacology , Glycogen Synthase Kinase 3/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Alzheimer Disease/drug therapy , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacology , Biological Assay , Drug Delivery Systems , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Fluorenes/chemical synthesis , Glycogen Synthase Kinase 3 beta , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Sf9 Cells , Structure-Activity RelationshipABSTRACT
Present Alzheimer's disease (AD) therapies suffer from inefficient effects on AD symptoms like memory or cognition, especially in later states of the disease. Used acteylcholine esterase inhibitors or the NMDA receptor antagonist memantine address one target structure which is involved in a complex, multifactorial disease progression. So the benefit for patients is presently poor. A more close insight in the AD progression identified more suggested target structures for drug development. Strategies of AD drug development concentrate on novel target structures combined with the established ones dedicated for combined therapy regimes, preferably by the use of one drug which may address two target structures. Protein kinases have been identified as promising target structures because they are involved in AD progression pathways like pathophysiological tau protein phosphorylations and amyloid ß toxicity. The review article will shortly view early inhibitors of single protein kinases like glycogen synthase kinase (gsk3) ß and cyclin dependent kinase 5. Novel inhibitors will be discussed which address novel AD relevant protein kinases like dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Moreover, multitargeting inhibitors will be presented which target several protein kinases and those which are suspected in influencing other AD relevant processes. Such a multitargeting is the most promising strategy to effectively hamper the multifactorial disease progression and thus gives perspective hopes for a future better patient benefit.
ABSTRACT
Alzheimer disease (AD) turned out to be a multifactorial process leading to neuronal decay. So far merely single target structures which attribute to the AD progression have been considered to develop specific drugs. However, such drug developments have been disappointing in clinical stages. Multitargeting of more than one target structure determines recent studies of developing novel lead compounds. Protein kinases have been identified to contribute to the neuronal decay with CDK1, GSK-3ß and CDK5/p25 being involved in a pathological tau protein hyperphosphorylation. We discovered novel lead structures of the dihydroxy-1-aza-9-oxafluorene type with nanomolar activities against CDK1, GSK-3ß and CDK5/p25. Structure-activity relationships (SAR) of the protein kinase inhibition are discussed within our first compound series. One nanomolar active compound profiled as selective protein kinase inhibitor. Bioanalysis of a harmless cellular toxicity and of the inhibition of tau protein phosphorylation qualifies the compound for further studies.
Subject(s)
Alzheimer Disease/enzymology , Aza Compounds/chemistry , Fluorenes/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , CDC2 Protein Kinase/antagonists & inhibitors , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Cyclin-Dependent Kinase 5/metabolism , Drug Evaluation, Preclinical , Fluorenes/chemical synthesis , Fluorenes/toxicity , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/toxicity , Protein Kinases/metabolism , Structure-Activity Relationship , tau Proteins/metabolismABSTRACT
A novel facile synthesis led to pyridine-2-one target structures of which first series with varying substituents have been yielded and biologically characterized as novel multidrug resistance (MDR) modulators inhibiting P-glycoprotein (P-gp). Structure-activity relationships prove a dependency of the MDR-modulating properties from the kind and positioning of hydrogen bond acceptor functions within the molecular skeleton. Cyano functions turned out as biologically effective substituents for a potential hydrogen bonding to the protein target structure.
