Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides

ABSTRACT: Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include N-methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism. GRAPHICAL ABSTRACT: [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10989-017-9590-8) contains supplementary material, which is available to authorized users.