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Methods Mol Med. 1999;23:37-51. doi: 10.1385/0-89603-517-4:37.

Synthesis of an esterase-sensitive cyclic prodrug of a model hexapeptide having enhanced membrane permeability and enzymatic stability using an acyloxyalkoxy promoiety.

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  • 1Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS.


The clinical development of orally active peptide drugs has been limited by their unfavorable physicochemical characteristics (e.g., charge, hydrogen bonding potential, size), which prevent them from permeating biological barriers such as the intestinal mucosa, and also their lack of stability against enzymatic degradation (1-12). Unfortunately, many of the structural features of peptides (i.e., the N-terminal amino group and C-terminal carboxyl group, and side chain carboxyl, amino, and hydroxyl groups) that bestow upon the molecule affinity and specificity for its pharmacological receptor severely restrict its ability to permeate biological barriers and make the molecules substrates for peptidases. Therefore, successful oral delivery of peptides depends on strategies designed to alter the physicochemical characteristics of these potential drugs without changing their biological activity in order to circumvent the intestinal epithelial cells.

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