Design, synthesis, and evaluation of stable and taste-free erythromycin proprodrugs.
Erythromycin A is normally formulated for children as its 2'-ethyl succinate, a taste-free prodrug. Unfortunately, the prodrug hydrolyzes at a measurable rate in the medicine bottle, leading to the vile-tasting erythromycin. We have prepared derivatives of erythromycin B as putative paediatric prodrugs, taking advantage of the much improved acid stability of erythromycin B relative to erythromycin A. Thus, erythromycin B enol ether ethyl succinate is very poorly soluble in water, and its hydrolysis is undetectable in conditions resembling the medicine bottle. In acid, however, it converts rapidly to erythromycin B 2'-ethyl succinate, and this is in turn hydrolyzed to erythromycin B in neutral and basic conditions. Derivatives of erythromycin B enol ether are therefore proposed as taste-free proprodrugs of erythromycin B.
Bhadra
Pranab K
PK
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PL, UK.
Morris
Gareth A
GA
Barber
Jill
J
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004355:Drug Stability; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008279:Magnetic Resonance Imaging; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D013649:Taste; D014867:Water
D000900:Anti-Bacterial Agents; D011355:Prodrugs; C501700:erythromycin B 2'-ethyl succinate; C501701:erythromycin B enol ether 2'-ethyl succinate; C501699:erythromycin B enol ethyl ether; D014867:Water; D004917:Erythromycin; C064662:berythromycin