Flurbiprofen (FLU) lipophilic prodrugs with lipoamino acids (LAA.), 6a-e were synthesized for brain delivery. Chemical and plasmatic-stability of prodrugs 6a-e as well as pharmacokinetic distribution studies for the prodrugs 6b and 6d were carried out. FLU prodrugs 6a-e were compared to the parent drug for their ability to inhibit binding of [F-18]FDDNP to in vitro formed P-amyloid protein (A beta fibrils). FLU-LAA conjugates showed a typical prodrug stability. profile, being stable in PBS at pH 7.4 and releasing the active drug in plasma. Compound 6d yielded a slow accumulation of FLU in the brain. In the in vitro inhibition assay, all prodrugs. except for the prodrug with the longest alkyl side chain (6e) were effective as inhibitors of [F-18]FDDNP binding to A beta fibrils with EC50 values in the 10-300 nM range. The different brain accumulation kinetics shown by FLU and its LAA conjugate 6d suggested a possible slow-releasing activity of FLU by these prodrugs in the brain or a differential pharmacological effect deserving further, detailed studies on their biodistribution and pharmacological profile.
|Titolo:||Flurbiprofen Derivatives in Alzheimer’s Disease: Synthesis, Pharmacokinetic and Biological Assessment of Lipoamino Acid Prodrugs|
|Data di pubblicazione:||2008|
|Appare nelle tipologie:||1.1 Articolo in rivista|