Design, synthesis and activity of ascorbic acid prodrugs of nipecotic, kynurenic and diclophenamic acids, liable to increase neurotropic activity.
To improve the entry of certain drugs into brain, ascorbic acid (AA) conjugates of these drugs were synthesized and their capacity to interact with SVCT2 ascorbate transporters was explored. Kinetic studies clearly indicate that all of the conjugates were able to competitively inhibit ascorbate transport in human retinal pigment epithelial cells (HRPE). In vivo studies, in a mouse model system, demonstrate that conjugate 3 is better absorbed compared to the nonconjugated parent drug.
Manfredini
Stefano
S
Pavan
Barbara
B
Vertuani
Silvia
S
Scaglianti
Martina
M
Compagnone
Donatello
D
Biondi
Carla
C
Scatturin
Angelo
A
Tanganelli
Sergio
S
Ferraro
Luca
L
Prasad
Puttur
P
Dalpiaz
Alessandro
A
D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry* / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004008:Diclofenac / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D007736:Kynurenic Acid / Q000737:chemistry*; D051379:Mice; D009557:Nipecotic Acids / Q000737:chemistry*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000188:drug therapy; D060347:Sodium-Coupled Vitamin C Transporters; D013329:Structure-Activity Relationship; D027981:Symporters
D002491:Central Nervous System Agents; D009557:Nipecotic Acids; D029363:Organic Anion Transporters, Sodium-Dependent; D011355:Prodrugs; D011506:Proteins; C555163:SLC23A2 protein, human; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; D004008:Diclofenac; C030278:nipecotic acid; D007736:Kynurenic Acid; D001205:Ascorbic Acid