RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Proteína Quinasa CDC2/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Fluorenos/química , Fluorenos/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Bioensayo , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Fluorenos/síntesis química , Glucógeno Sintasa Quinasa 3 beta , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Células Sf9 , Relación Estructura-ActividadRESUMEN
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.