New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on beta-Amyloid Levels
Özet
Alzheimer's disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate gamma-secretase, reducing beta amyloid (A beta) levels, have been considered as potential therapeutics for AD. Among these the (R)-enantiomer of flurbiprofen (FLU) seems to be very promising, but it shows low brain penetration. In this study, in order to improve the properties of FLU against Alzheimer's pathogenesis we synthesized some novel FLU lipophilic analogues. Lipophilicity of the new molecules has been characterized in terms of clogP, log K-C18/W and log K (IAM/W) values. Permeability has been determined in both gastrointestinal PAMPA (PAMPA-GI) at different pH values and in brain blood barrier PAMPA (PAMPA-BBB) models. They were also tested for their ability to inhibit in vitro gamma-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce A beta 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.
Anahtar kelimeler
Atıf için künye
Sozio, P., Marinelli, L., Cacciatore, I., Fontana, A., Türkez, H., Giorgioni, G., Ambrosini, D., Barbato, F., Grumetto, L., Pacella, S., Cataldi, A., & Di Stefano, A. (2013). New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on beta-Amyloid Levels. MOLECULES, 18(9), 10747–10767. https://doi.org/10.3390/molecules180910747
BibTeX
@article{sozio2013-245007,
author = {Sozio, Piera and Marinelli, Lisa and Cacciatore, Ivana and Fontana, Antonella and Türkez, Hasan and Giorgioni, Gianfabio and Ambrosini, Dario and Barbato, Francesco and Grumetto, Lucia and Pacella, Stephanie and Cataldi, Amelia and Di Stefano, Antonio},
title = {New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on beta-Amyloid Levels},
journal = {MOLECULES},
year = {2013},
volume = {18},
number = {9},
pages = {10747--10767},
issn = {1420-3049},
doi = {10.3390/molecules180910747},
url = {https://akademik.atauni.edu.tr/yayinlar/245007-new-flurbiprofen-derivatives-synthesis-membrane-affinity-and-evaluation-of-in}
}