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

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          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 clog P, 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.

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          NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.

          Jason Eriksen, Sarah Sagi, Tawnya Smith … (2003)
          Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.
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            Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract.

            D Hörter, J B Dressman (2001)
            The rate-limiting step to absorption of drugs from the gastrointestinal (GI) tract is often dissolution from the dosage form. Consideration of the Noyes-Whitney dissolution model shows that drug diffusivity, solubility in the gastrointestinal contents, the surface area of the solid wetted by the lumenal fluids and the GI hydrodynamics all play a role in determining the in vivo dissolution rate. Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity, solubilization by native surfactants and co-ingested foodstuffs, and pK(a) in relation to the GI pH profile. Compounds with aqueous solubilities lower than 100 microg/ml often present dissolution limitations to absorption. The dose:solubility ratio of the drug provides an estimate of the volume of fluids required to dissolve an individual dose, and when this volume exceeds 1 l, dissolution is often problematic. The surface area of a drug available for dissolution depends on the particle size of the solid and its ability to be wetted by lumenal fluids. Other physiological factors that can play a role in dissolution include the viscosity of the lumenal contents, through its effect on the diffusivity, and mixing and flow patterns within the gut. In order to better predict in vivo dissolution of drugs, dissolution tests which more adequately simulate the physiological conditions are needed.
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              γ-Secretase inhibitors and modulators for Alzheimer's disease.

              Michael S. Wolfe (2012)
              γ-Secretase is a membrane embedded aspartyl protease complex with presenilin as the catalytic component. Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure. However, these compounds have served as useful chemical tools for biological investigations. In contrast, γ-secretase modulators continue to be of keen interest as possible AD therapeutics. These modulators either shift amyloid β-protein production to shorter, less pathogenic peptides or inhibit the proteolysis of amyloid β-protein precursor selectively compared to that of Notch. The various chemical types of inhibitors and modulators will be discussed, along with their use as probes for basic biology and their potential as AD therapeutics. © 2011 The Author. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 03 September 2013
                Publication date Collection: September 2013
                Volume: 18
                Issue: 9
                Pages: 10747-10767
                Affiliations
                [1 ]Department of Pharmacy, “G. D’Annunzio” University, Via dei Vestini 31, Chieti 66100, Italy
                [2 ]Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey
                [3 ]Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, via S. Agostino 1, Camerino 62032, Italy
                [4 ]Center for Drug Discovery 116 MU, Northeastern University, 360 Huntington Avenue, Boston 02115-5000, MA, USA
                [5 ]Department of Pharmacy, Università di Napoli Federico II, Via D. Montesano 49, Naples 80131, Italy
                [6 ]Department of Medicine and Ageing Sciences, “G. D’Annunzio” University, Via dei Vestini 31, Chieti 66100, Italy
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: p.sozio@ 123456unich.it ; Tel.: +39-871-3554-709; Fax: +39-871-3554-706.
                Article
                Publisher ID: molecules-18-10747
                DOI: 10.3390/molecules180910747
                PMC ID: 6270570
                PubMed ID: 24005968
                SO-VID: 1d214a27-0762-4b05-bd1e-6331c89e82ee
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 28 June 2013
                Date revision received : 14 August 2013
                Date accepted : 27 August 2013
                Categories
                Subject: Article

                Keywords: alzheimer’s disease,beta amyloid peptide,flurbiprofen,γ-secretase
                Data availability:
                Keywords: alzheimer’s disease, beta amyloid peptide, flurbiprofen, γ-secretase

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