Evaluation of phenyl carbamates of ethyl diamines as cyclization-activated prodrug forms for protecting phenols against first-bass metabolism

Add time:07/24/2019    Source:sciencedirect.com

A series of phenyl N-(2-aminoethyl)carbamates derived from various substituted ethyl diamines and phenol was prepared and evaluated as prodrug forms with the aim of protecting phenolic drugs against first-pass metabolism. The stability of the compounds was studied in aqueous buffer solutions and in various biological media. The compounds showed a high stability at lower pH but degraded by a cyclization process at higher pH values with a quantitative release of the parent phenol. The rate of cyclization was not affected by plasma, liver or gut enzymes but depended on the pH value of the medium and on the steric properties of the various substituents. By appropriate selection of the substituents, it is readily feasible to obtain prodrug derivatives having useful rates of cyclization, and hence release of the parent phenolic drug at pH 7.4 and 37°C, corresponding to half-lives of 10–60 min. The results suggest that this prodrug principle involving a non-enzymatic but pH-dependent conversion may be a potentially useful approach to reduce the extent of first-pass metabolism of the vulnerable phenol group.

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