Recently Non Steroidal Antiinflammatory Drugs (NSAIDs) has been proposed to prevent or to cure Alzheimer’s disease. In this respect, we synthesized new 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, that acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. Lipophilicity of all prepared prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic Rm value, and with predictive computational methods. From experimental parameter, all prodrugs resulted more lipophile if compared to the corresponding parent compounds and hence for them a better blood brain barrier (BBB) penetration is hypothised. Prodrug lipophilicity was correlated with a calculated LogP value according to Kowwin method. The correlation between experimental R0m and calculated Log P, determined by PLS analisys, was good for all compounds with the exception of 7i. At last the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted good candidates for BBB penetration
Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to CNS
PERIOLI, Luana;AMBROGI, Valeria;GRANDOLINI, Giuliano;RICCI, Maurizio;GIOVAGNOLI, Stefano;ROSSI, Carlo
2004
Abstract
Recently Non Steroidal Antiinflammatory Drugs (NSAIDs) has been proposed to prevent or to cure Alzheimer’s disease. In this respect, we synthesized new 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, that acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. Lipophilicity of all prepared prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic Rm value, and with predictive computational methods. From experimental parameter, all prodrugs resulted more lipophile if compared to the corresponding parent compounds and hence for them a better blood brain barrier (BBB) penetration is hypothised. Prodrug lipophilicity was correlated with a calculated LogP value according to Kowwin method. The correlation between experimental R0m and calculated Log P, determined by PLS analisys, was good for all compounds with the exception of 7i. At last the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted good candidates for BBB penetrationI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
