期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 13, 页码 6774-6783出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00013
关键词
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资金
- Bayer AG
- Natural Sciences and Engineering Research Council of Canada [RGPIN 201705513]
- Canadian Foundation for Innovation
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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