Journal of Medicinal Chemistry p. 6774 - 6783 (2020)
Update date:2022-08-05
Topics:
Le Roux, Antoine
Blaise, émilie
Boudreault, Pierre-Luc
Comeau, Christian
Doucet, Annie
Giarrusso, Marilena
Collin, Marie-Pierre
Neubauer, Thomas
K?lling, Florian
G?ller, Andreas H.
Seep, Lea
Tshitenge, Dieudonné T.
Wittwer, Matthias
Kullmann, Maximilian
Hillisch, Alexander
Mittendorf, Joachim
Marsault, Eric
We herein report the first thorough analysis of the structure-permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay. Structural variations led to tractable structure-permeability and structure-efflux relationships, wherein the linker length, stereoinversion, N-methylation, and peptoids site-specifically impact the permeability and efflux. Extensive nuclear magnetic resonance, molecular dynamics, and ensemble-based three-dimensional polar surface area (3D-PSA) studies showed that ensemble-based 3D-PSA is a good predictor of passive permeability.
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