Though non-steroidal anti-inflammatory drugs (NSAIDs) have shown prophylactic efficacy against Alzheimer’s disease (AD), they have shown little efficacy as treatments. Certain NSAIDs (e.g., flurbiprofen) have the potential to treat AD, based on their anti-inflammatory properties and abilities to target β-amyloid aggregation; however, their low brain bioavailabilities have, in part, limited their clinical efficacy. Our group has synthesized a series of hydrophobic, small molecule NSAID conjugates containing ester, amide, carbonate and carbamate linkages and an N-benzylamide BBB shuttle. A parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB) was used to predict the effective permeabilities (Pe) of some of these novel conjugates. The in vitro stabilities in human plasma (pH 7.4) were also assessed. An (S)-naproxen carbamate derivative exhibited a 20-fold increased rate of BBB permeability compared to the NSAID alone and could serve as a lead compound for the development of brain-bioavailable AD treatments.

Predicted blood-brain barrier permeabilities for carbonate and carbamate-containing non-steroidal anti-inflammatory drug conjugates

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