New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on β-Amyloid Levels

Molecules

Piera Sozio²  Lisa Marinelli²  Ivana Cacciatore²  Antonella Fontana²  Hasan Türkez⁴  Gianfabio Giorgioni¹  Dario Ambrosini⁶  Francesco Barbato³  Lucia Grumetto³  Stephanie Pacella⁵  Amelia Cataldi² 

[1] Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, via S. Agostino 1, Camerino 62032, Italy;Department of Pharmacy, “G. D’Annunzio” University, Via dei Vestini 31, Chieti 66100, Italy;Department of Pharmacy, Università di Napoli Federico II, Via D. Montesano 49, Naples 80131, Italy;Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey;Department of Medicine and Ageing Sciences, “G. D’Annunzio” University, Via dei Vestini 31, Chieti 66100, Italy;Center for Drug Discovery 116 MU, Northeastern University, 360 Huntington Avenue, Boston 02115-5000, MA, USA

关键词: Alzheimer’s disease;    beta amyloid peptide;    flurbiprofen;    γ-secretase;   

DOI  :  10.3390/molecules180910747

来源: mdpi

【 摘 要 】

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 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 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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.