Cyclic Penta- and Hexaleucine Peptides without N -Methylation Are Orally Absorbed
ACS Medicinal Chemistry Letters2014Vol. 5(10), pp. 1148–1151
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Timothy A. Hill, Rink‐Jan Lohman, Huy N. Hoang, Daniel S. Nielsen, Conor C. G. Scully, W. Mei Kok, Ligong Liu, Andrew J. Lucke, Martin J. Stoermer, Christina I. Schroeder, Stephanie Chaousis, Barbara Colless, Paul V. Bernhardt, David J. Edmonds, David A. Griffith, Charles J. Rotter, Roger B. Ruggeri, David A. Price, Spiros Liras, David J. Craik, David P. Fairlie
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.
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