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Viayna, Elisabet; Sola, Irene; Bartolini, Manuela; De Simone, Angela; Tapia-Rojas, Cheril; Serrano, Felipe G; Sabaté, Raimon; Juárez-Jiménez, Jordi; Pérez, Belén; Luque, F Javier; Andrisano, Vincenza; Clos, M Victòria; Inestrosa, Nibaldo C; Muñoz-Torrero, Diego
Journal of medicinal chemistry, 2014-Mar-27, Letnik: 57, Številka: 6Journal Article
We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Aβ42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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