Discovery of a "true" aspirin prodrug.
Aspirin prodrugs formed by derivatization at the benzoic acid group are very difficult to obtain because the promoiety accelerates the rate of hydrolysis by plasma esterases at the neighboring acetyl group, generating salicylic acid derivatives. By tracing the hydrolysis pattern of the aspirin prodrug isosorbide-2,5-diaspirinate (ISDA) in human plasma solution, we were able to identify a metabolite, isosorbide-2-aspirinate-5-salicylate, that undergoes almost complete conversion to aspirin by human plasma butyrylcholinesterase, making it the most successful aspirin prodrug discovered to date.
Moriarty
Louise M
LM
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Lally
Maeve N
MN
Carolan
Ciaran G
CG
Jones
Michael
M
Clancy
John M
JM
Gilmer
John F
JF
D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002091:Butyrylcholinesterase / Q000097:blood; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004952:Esters / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007547:Isosorbide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008956:Models, Chemical; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013696:Temperature; D013997:Time Factors
D004952:Esters; D011355:Prodrugs; C534491:isosorbide-2,5-diaspirinate; D002091:Butyrylcholinesterase; D001241:Aspirin; D007547:Isosorbide