Beta-aminoketones as prodrugs with pH-controlled activation.
N-Mannich bases have been widely applied as prodrugs of amine drugs. The analogous C-Mannich bases (beta-aminoketones) have received rather less attention probably because they are not sufficiently susceptible to elimination at pHs encountered in vivo. Compounds in which there is a thermodynamic advantage to elimination may be an exception. In this study, the physicochemical characteristics of a series of Michael amino addition adducts of chalcone and other carbonyl compounds is explored. The ketone adducts rapidly eliminate at around pH 7.4 (t(1/2) < 15 min) releasing the amine and the ketone but they are stable under acidic conditions. The Michael adducts are more lipophilic than the parent amines and have significantly suppressed ionisation characteristics at biologically relevant pH values.
Simplício
Ana Luísa
AL
School of Pharmacy, Trinity College, Dublin 2, Ireland. anas@itqb.unl.pt
Clancy
John M
JM
Gilmer
John F
JF
D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D019075:Electrophoresis, Capillary; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008352:Mannich Bases / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D000588:Amines; D007659:Ketones; D008352:Mannich Bases; D011355:Prodrugs