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Structure-Permeability Relationship of Semipeptidic Macrocycles-Understanding and Optimizing Passive Permeability and
Antoine Le Roux1, Émilie Blaise1, Pierre-Luc Boudreault1
1Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec J1H 5N4, Canada.
Journal of Medicinal Chemistry
|May 27, 2020
Summary
This study reveals how semipeptidic macrocycle structure affects cell permeability. Ensemble-based 3D-PSA effectively predicts passive permeability, while efflux influences cellular transport.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Chemical Biology
Background:
- Semipeptidic macrocycles are promising drug candidates.
- Understanding their structure-permeability relationship is crucial for drug development.
Purpose of the Study:
- To analyze the structure-permeability relationship of semipeptidic macrocycles.
- To identify key structural factors influencing permeability and efflux.
Main Methods:
- Synthesis of 47 semipeptidic macrocycles using a hybrid solid-phase/solution strategy.
- Assessment of passive permeability using parallel artificial membrane permeability assay (PAMPA).
- Evaluation of cellular permeability using Caco-2 assay.
Main Results:
- Semipeptidic macrocycles exhibit high passive permeability (PAMPA).
- Cellular permeability is significantly influenced by efflux mechanisms (Caco-2 assay).
- Linker length, stereoinversion, N-methylation, and peptoid modifications impact permeability and efflux.
Conclusions:
- Ensemble-based 3D-PSA is a reliable predictor of passive permeability for semipeptidic macrocycles.
- Efflux is a critical determinant of cellular permeability for these compounds.
- Structure-activity relationships were established for optimizing semipeptidic macrocycle drug design.
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