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

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.

Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells

“…Endocytosis of adhesion proteins has been shown to play a role in the disassembly of adhesion complexes (Alarcos et al, 2015;Bockus et al, 2015;Jin et al, 2015;Kowalczyk and Nanes, 2012;Mosesson et al, 2008;Xiao et al, 2005); however, the mechanism by which Cad11 is internalized is unknown. In this study, we identified proteins that interact with the cytoplasmic domain of Cad11 and found that clathrin is one of the Cad11-interacting proteins.…”

Leveraging chromatography based physicochemical properties for efficient drug design

“…Bockus et al used Elog D (5.5 to 7.5) to study macrocycles. The lipophilicity values correlated with cell-based permeability values by Madin-Darby canine kidney (MDCK)-low efflux cells (MDCK-LE) [38].…”

“…Since its introduction, it has been used successfully in a traditional chemistry space [22,[56][57][58][59][60] as well as in the bRo5 programs [38].…”

“…At Pfizer, and across multiple academic collaborations [38,[89][90][91], project teams routinely use EPSA data to inform peptide design as a predictor of permeability and as an indicator of IMHB patterns in cyclic peptides. Furthermore, EPSA is now used in a prospective way after the development of an in-house computational model [92].…”

Versatile Multicomponent Reaction Macrocycle Synthesis Using α-Isocyano-ω-carboxylic Acids

“…Three examples in Figure 2 (9.1, 9.9, and 9.10) exemplify the potential of intramolecular hydrogen bonding to potentially stiffen the macrocycle and to also increase hydrophobicity, a mechanism recently reported to increase bioavailability of macrocycles. 22 In particular, the introduction of γ-amino acid linkers such as in 9.1, 9.9, and 9.10 has been recognized to increase passive membrane penetration through intramolecular hydrogen bonding. Another important recent finding is that selective N-alkylation of amide groups in the macrocycle can also increase membrane penetration.…”