Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable |
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| Authors: | Daniel S. Nielsen Dr. Huy N. Hoang Dr. Rink‐Jan Lohman Dr. Timothy A. Hill Dr. Andrew J. Lucke Prof. Dr. David J. Craik Dr. David J. Edmonds Dr. David A. Griffith Charles J. Rotter Dr. Roger B. Ruggeri Dr. David A. Price Dr. Spiros Liras Prof. Dr. David P. Fairlie |
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| Affiliation: | 1. Division of Chemistry and Structural Biology, University of Qld, Brisbane, Qld 4072 (Australia);2. World Wide Medicinal Chemistry, CVMED, Pfizer, Cambridge, MA (USA);3. Pfizer Pharmacokinetics, Dynamics and Metabolism, Groton, CT (USA) |
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| Abstract: | The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR‐derived structures, amide H–D exchange rates, and temperature‐dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N‐methylation. |
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| Keywords: | cyclic peptides NMR oral bioavailability permeability |
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