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New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on β-Amyloid Levels
Department of Pharmacy, "G. D'Annunzio" University, Via dei Vestini 31, Chieti 66100, Italy
Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey
Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, via S. Agostino 1, Camerino 62032, Italy
Center for Drug Discovery 116 MU, Northeastern University, 360 Huntington Avenue, Boston 02115-5000, MA, USA
Department of Pharmacy, Università di Napoli Federico II, Via D. Montesano 49, Naples 80131, Italy
Department of Medicine and Ageing Sciences, "G. D'Annunzio" University, Via dei Vestini 31, Chieti 66100, Italy
* Author to whom correspondence should be addressed.
Received: 28 June 2013; in revised form: 14 August 2013 / Accepted: 27 August 2013 / Published: 3 September 2013
Abstract: 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 γ-secretase, reducing β amyloid (Aβ) 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 KC18/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 γ-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce Aβ 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.
Keywords: Alzheimer’s disease; beta amyloid peptide; flurbiprofen; γ-secretase
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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. New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on β-Amyloid Levels. Molecules 2013, 18, 10747-10767.
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. New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on β-Amyloid Levels. Molecules. 2013; 18(9):10747-10767.
Sozio, Piera; Marinelli, Lisa; Cacciatore, Ivana; Fontana, Antonella; Türkez, Hasan; Giorgioni, Gianfabio; Ambrosini, Dario; Barbato, Francesco; Grumetto, Lucia; Pacella, Stephanie; Cataldi, Amelia; Di Stefano, Antonio. 2013. "New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on β-Amyloid Levels." Molecules 18, no. 9: 10747-10767.