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J Med Chem. 2015 Jun 11;58(11):4581-9. doi: 10.1021/acs.jmedchem.5b00128. Epub 2015 May 20.

Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products.

Author information

1
†Department of Chemistry and Biochemistry, University of California-Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States.
2
‡Department of Pharmaceutical Chemistry, University of California- San Francisco, 1700 4th Street, San Francisco, California 94158, United States.
3
§Pharmacokinetics and Drug Metabolism, Pfizer Inc., Groton, Connecticut 06340, United States.
4
∥Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States.

Abstract

Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure-permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.

PMID:
25950816
DOI:
10.1021/acs.jmedchem.5b00128
[Indexed for MEDLINE]

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