Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products
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- 作者：Andrew T. Bockus ; Katrina W. Lexa ; Cameron R. Pye ; Amit S. Kalgutkar ; Jarret W. Gardner ; Kathryn C. R. Hund ; William M. Hewitt ; Joshua A. Schwochert ; Emerson Glassey ; David A. Price ; Alan M. Mathiowetz ; Spiros Liras ; Matthew P. Jacobson ; R. Scott Lokey
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 11, 2015
- 年：2015
- 卷：58
- 期：11
- 页码：4581-4589
- 全文大小：362K
- ISSN：1520-4804
文摘
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as lass="smallcaps">d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate 纬-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 纬-amino acids (e.g., statines) and systematically investigate their structure鈥損ermeability 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 纬-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.