Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to the CNS.
Recently non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed to prevent or to cure Alzheimer's disease. In this respect, we synthesized new potential prodrugs of several NSAIDs in order to increase their access to the brain. The carboxylic group of NSAIDs was attached to the 1,4-dihydro-1-methylpyridine-3-carboxylate moiety, which acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. The lipophilicity of potential prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic R(m) value, and by predictive computational methods. From experimental parameters, all prodrugs were more lipophilic when compared to their corresponding parent compounds and consequently a better blood brain barrier (BBB) penetration is hypothesised. Prodrug lipophilicity was correlated with a calculated log P value according to Kowwin's method. The correlation between experimental Rm0 and calculated log P, determined by PLS analysis, was good for all compounds with the exception of compound 7i. In addition the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted in good candidates for BBB penetration.
Dipartimento di Chimica e Tecnologia del Farmaco, Via del Liceo 1, Università degli Studi di Perugia, 06123 Perugia, Italy. luanaper@unipg.it
Luana
L
Perioli
Valeria
V
Ambrogi
Claudia
C
Bernardini
Giuliano
G
Grandolini
Maurizio
M
Ricci
Stefano
S
Giovagnoli
Carlo
C
Rossi
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods*; D010539:Permeability / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs