PEPTIDE ESTERS AS WATER-SOLUBLE PRODRUGS FOR HYDROXYL CONTAINING AGENTS - CHEMICAL-STABILITY AND ENZYMATIC-HYDROLYSIS OF BENZYL-ESTERS OF GLYCINE, DIGLYCINE AND TRIGLYCINE

The chemical stability and enzymatic hydrolysis of the mono-, di- and triglycine esters of benzyl alcohol were studied to assess the potential usefulness of peptide esters as water-soluble prodrugs for agents containing a hydroxyl group. All esters were readily hydrolyzed in 80% human plasma to give benzyl alcohol, the half-lives being 69 min for the glycine ester, 17 min for the diglycine ester and 58 min for the triglycine ester. The hydrolysis of the latter ester occurred by a two step reaction with the diglycine ester as an intermediate. The pH-rate profiles for the degradation of the esters in aqueous solution were obtained at 60-degrees-C. Maximal stability occurred at pH 3-4 at which pH the esters are highly water-soluble. The stability of the di- and triglycine esters at pH 3-5 were not markedly different and only slightly higher than that of the glycine ester. Therefore, di- and tripeptide ester prodrugs do not appear to possess significant advantages over alpha-amino acid esters in terms of chemical stability. From temperature-accelerated studies, the shelf-life (t10%) of an aqueous soluiton (pH 4) of the triglycine ester was thus predicted to be only 8 days at 25-degrees-C.