Development of a Platform To Enable Efficient Permeability Evaluation of Novel Organo-Peptide Macrocycles

As more macrocycle structures are utilized to drug intracellular targets, new platforms are needed to facilitate the discovery of cell permeable compounds in this unique chemical space. Herein, a method is disclosed that allows for the efficient synthesis and permeability evaluation of novel organo-...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2019-06, Vol.10 (6), p.874-879
Main Authors: Hopkins, Brett A, Lee, Hyelee, Ha, Sookhee, Nogle, Lisa, Sauvagnat, Berengere, McMinn, Spencer, Smith, Graham F, Sciammetta, Nunzio
Format: Article
Language:English
Subjects:
Letter
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:As more macrocycle structures are utilized to drug intracellular targets, new platforms are needed to facilitate the discovery of cell permeable compounds in this unique chemical space. Herein, a method is disclosed that allows for the efficient synthesis and permeability evaluation of novel organo-peptide macrocycle libraries. Thoughtful library design allows for the collection of crude permeability data using supercritical fluid chromatography mass spectrometry (SFC-MS) (EPSA) by mass-encoding the stereochemistry, ring size, and organic linker of the desired macrocycles. Library synthesis was aided via the development of a new on-resin N-arylation reaction. Further insights on the permeation of these organo-peptide macrocycles will be discussed, such as the permeability enhancement when utilizing a 2-substituted phenethyl linker versus a 3-substituted phenethyl linker. Lastly, selected macrocycles were scaled up and tested in the MDCK-II permeability assay, and the results of this assay reiterated the permeability trends from the crude SFC-MS data.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.9b00036