Novel brain targeting prodrugs of naproxen based on dimethylamino group with various linkages.

As a preventive and treatment drug for Alzheimer's disease (AD), naproxen's clinical application is hampered by its limited distribution in the brain. To increase the delivery of naproxen across the blood-brain barrier (BBB), 3 prodrugs (P1, P2 and P3) of naproxen were synthesized through either ester bond or amido bond using the dimethylamino moiety as a brain-targeting ligand. The in vitro release of naproxen from the 3 prodrugs was studied in PBS, rat plasma and brain homogenate. P3 with an amido bond appeared to be highly stable in all incubation media, whereas P1 and P2 with ester bonds were partially hydrolyzed in alkaline environment and brain homogenate to yield the parent drug. After i. v. administration to rats, the brain concentration of total naproxen (summation of released and bound naproxen, TN) of P1, P2 and P3 groups were 28.81, 24.51 and 15.54 times greater than that of the control naproxen group at 5 min, respectively, and the brain AUC0-t were 6.94, 10.06 and 6.70 times greater than that of the control naproxen group. In addition, the Cmax of TN in the brain after the administration of prodrugs with ester bonds (P1 and P2) was higher than that of the amide prodrug (P3). The results highlighted the possibility of brain delivery of naproxen using prodrug strategies based on the brain-targeting ligand with dimethylamino moiety, in which the linkage between drug and targeting group might play an important role in modulating the in vivo behaviors of these prodrugs.