Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity
| Autor: | R. Scott Lokey, Victoria G. Klein, Daigo Asano, Quinn Edmondson, Cameron R. Pye, Akihiro Furukawa, Joshua Schwochert, Satoshi Ono, Okimasa Okada, Alexandra C Turmon |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
Macrocyclic Compounds Molecular Structure Membrane permeability 010405 organic chemistry Peptoid General Medicine General Chemistry 010402 general chemistry 01 natural sciences Combinatorial chemistry Article Catalysis Cyclic peptide Chemical space 0104 chemical sciences Molecular Weight chemistry.chemical_compound Rigidity (electromagnetism) chemistry Lipophilicity Side chain Peptides Hydrophobic and Hydrophilic Interactions ADME |
| Zdroj: | Angew Chem Int Ed Engl |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202004550 |
| Popis: | Large, macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable, cross-β conformations, and found that peptoid substitutions within the β-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing β-strands led to “chameleonic” species that were rigid in nonpolar media but highly flexible in water. Both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune optimal lipophilicity. |
| Databáze: | OpenAIRE |
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