Microwave-assisted synthesis and in vitro stability of N-benzylamide non-steroidal anti-inflammatory drug conjugates for CNS delivery

More effective delivery of non-steroidal anti-inflammatory drugs (NSAIDs) to the brain could treat the underlying inflammatory pathology of a range of CNS diseases and conditions. Use of a blood-brain barrier shuttle such as the N-benzylamide moiety, which has been largely unexplored for this purpose, could improve the brain bioavailabilities of NSAIDs. A series of novel N-benzylamide NSAID conjugates was synthesized via a three-step process with a microwave-assisted bimolecular nucleophilic substitution as the final step. We explored conditions to promote substitution over a competing elimination reaction, which was successfully suppressed with isopropyl alcohol solvent. All molecules exhibit physicochemical properties consistent with those of brain-penetrant molecules. Furthermore, they exhibit long ( > 48 h) half-lives in phosphate-buffered saline (PBS; pH 7.4) and short to moderate half-lives in human plasma. N-Benzylamide NSAID conjugates represent promising CNS drug discovery leads.