Acetaminophen Prodrugs I. Synthesis, Physicochemical Properties, and Analgesic Activity

Abstract

Carbonate and carboxylic acid ester prodrugs of acetaminophen were prepared. As expected, they had lower water solubilities and higher oil/water partition coefficients than acetaminophen itself. At pH 7.4 the prodrugs were slowly hydrolyzed in phosphate buffer, but human plasma enzymes markedly accelerated the hydrolyses. The LD50's of some of the compounds in mice suggest that, following oral administration, their solubility properties play a greater part in controlling the availability of acetaminophen than do their hydrolysis rates. Several of the compounds were found to have weak analgesic activity orally in rats supporting the theory that their analgesic activities and toxicities are due to release of acetaminophen. The results show how the carbonate linkage may be employed to create prodrugs and how it is possible to obtain a series of pharmacologically similar compounds possessing vastly different physicochemical properties. Carbonate and carboxylic acid ester prodrugs of acetaminophen were prepared. As expected, they had lower water solubilities and higher oil/water partition coefficients than acetaminophen itself. At pH 7.4 the prodrugs were slowly hydrolyzed in phosphate buffer, but human plasma enzymes markedly accelerated the hydrolyses. The LD50's of some of the compounds in mice suggest that, following oral administration, their solubility properties play a greater part in controlling the availability of acetaminophen than do their hydrolysis rates. Several of the compounds were found to have weak analgesic activity orally in rats supporting the theory that their analgesic activities and toxicities are due to release of acetaminophen. The results show how the carbonate linkage may be employed to create prodrugs and how it is possible to obtain a series of pharmacologically similar compounds possessing vastly different physicochemical properties.