Author(s): Hill TA, Lohman RJ, Hoang HN, Nielsen DS, Scully CC,
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Abstract Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17\%) approaching that of the heavily N-methylated drug cyclosporine (22\%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.
This article was published in ACS Med Chem Lett
and referenced in Medicinal Chemistry