Novel polycyclic analogues of non–steroidal anti–inflammatory drugs for increased blood–brain barrier permeability
Van den Berg, Marli
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Various recent studies have confirmed that inflammation plays a key role in the pathogenesis of neurodegenerative disorders like Alzheimer's disease and Parkinson's disease. In this study the focus was on delivery to the brain of certain non-steroidal anti-inflammatory drugs (NSAIDs), as a possible treatment for neurodegeneration, due to their anti-inflammatory and antioxidant activity. The blood-brain barrier (BBB) plays the predominant role in controlling the passage of substances between the blood and the brain. There are certain physicochemical characteristics necessary for a compound to cross the BBB. NSAIDs, for example, ibuprofen and acetylsalicylic acid are relatively hydrophilic and does not cross the blood-brain barrier in sufficient amounts to reach therapeutic concentrations in the central nervous system (CNS). Studies done on polycyclic cage structures, for example pentacyclo [5.4.0.02,6.03,10 0.05,9] undecane, indicated favourable distribution to the brain and it was concluded that these polycyclic structures penetrate the BBB readily. It was therefore hypothesised that the polycyclic cage compounds could be used as carrier molecules to enhance the delivery of neuroprotective compounds into the CNS and the aim of this study was to design novel polycyclic structures incorporating selected NSAIDs in order to improve their blood-brain barrier permeability. The well-described Cooksen's diketone, pentacyclo [5.4.0.02,6.03,10 0.05,9] undecane-8,11 dione, was conjugated to 2-aminoethanol by means of reductive amination. This gave a pentacycloundecylamine with a sterically free linker section. In the relevant compounds, the hydroxyl group on the linker was then conjugated to the benzoic acid moiety to yield the respective ester prodrugs. This esterfication was done using the activation agent, 1-ethyl-3(3'-dimethylamino) carbodiimide (EDC) to activate the benzoic acid group on ibuprofen and by using the commercially available acid chloride derivative of acetylsalicylic acid. Amide prodrug syntheses were done by conjugating the 1\1 SA I Os to 1, 2-diaminoethane by means of Fischer-esterfication and aminolysis reactions. Structure elucidation was done using one dimensional nuclear magnetic resonance (NMR). infrared (IR) absorption spectroscopy and mass spectrometry (MS). An in vivo BBB permeability assay employing HPLC analytical procedures was used to compare blood and brain concentrations of the relevant drugs 15 min, 30 min and 60 min after administration to the male C57BU6 mice. The antioxidant activities of the compounds were assessed with the in vitro Thiobarbituric Acid (TBA) assay. Both NSAI Ds were detected in the brain tissue of test mice, indicating blood-brain barrier permeation. The ester prod rugs were found to be very labile and significant amounts of it were hydrolysed. When administering these ester prodrugs (compound 11 and 12), the free NSAIDs were detected at higher concentrations compared to when the free drugs were administered. The amide compounds (compounds 15 and 17) were found to be toxic during administering of the prodrugs to the mice and were not further investigated. Lipid peroxidation results indicated that the ester compounds marginally increased the ability of the free drugs to attenuate lipid peroxidation, but not to the level of the model antioxidant Trolox and is therefore not significant. The novel synthesised prod rugs therefore present with a possible multiple drug targeting action as the blood-brain barrier permeability and the antioxidant activity of the free NSAIDs were increased.
- Health Sciences