Abstract
A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 - 12.5) at 37 degrees C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from omega-hydroxy carboxylic acids with longer alkyl chains. The carbonate esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics.
Highlights
A major cause of failures in early drug development is, together with toxicological issues, poor drug pharmacokinetics
With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving pharmacokinetics we have studied a series of bioreversible derivatives of phenol [26]
The carbonate esters with fatty acid-like structure were synthesized from phenyl chloroformate and the appropriate ω-hydroxycarboxylic acids or ethyl ester of the ω-hydroxycarboxylic acids, essentially following the procedures described by King et al [36]
Summary
A major cause of failures in early drug development is, together with toxicological issues, poor drug pharmacokinetics. In the current work we present the synthesis procedures and the obtained pH rate profiles for the hydrolysis of a series of carbonate esters of phenol encompassing derivatives with fatty acid-like structures. In the pH range investigated, the shape of the pH-rate profiles of compounds 1, 2 and 9 indicates that the pseudo-first-order rate constant at zero buffer concentration can be adequately described by specific acid, specific base, and spontaneous or water catalyzed hydrolysis reactions: k
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