Flurbiprofen derivatives in Alzheimer's disease: synthesis, pharmacokinetic and biological assessment of lipoamino acid prodrugs.
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 beta-amyloid protein (Abeta 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 Abeta 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.
Pignatello
Rosario
R
Dipartimento di Scienze Farmaceutiche Università degli Studi di Catania, Viale A. Doria, 6 - 95125 Catania, Italy. r.pignatello@unict.it
Pantò
Valentina
V
Salmaso
Stefano
S
Bersani
Sara
S
Pistarà
Venerando
V
Kepe
Vladimir
V
Barrio
Jorge R
JR
Puglisi
Giovanni
G
D000544:Alzheimer Disease / Q000188:drug therapy*; D000596:Amino Acids / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D007275:Injections, Intravenous; D051379:Mice; D009570:Nitriles / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use
C444520:2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile; D000596:Amino Acids; D016229:Amyloid beta-Peptides; D003692:Delayed-Action Preparations; D009570:Nitriles; D011355:Prodrugs; D005480:Flurbiprofen