Modulation of the Passive Permeability of Semipeptidic Macrocycles: N- and C-Methylations Fine-Tune Conformation and Properties

被引：14

作者：

Comeau, Christian ^{[1
]}

Ries, Benjamin ^{[2
]}

Stadelmann, Thomas ^{[2
]}

Tremblay, Jacob ^{[1
]}

Poulet, Sylvain ^{[1
]}

Frohlich, Ulrike ^{[1
]}

Cote, Jerome ^{[1
]}

Boudreault, Pierre-Luc ^{[1
]}

Derbali, Rabeb Mouna ^{[3
]}

Sarret, Philippe ^{[1
]}

Grandbois, Michel ^{[1
]}

Leclair, Gregoire ^{[3
]}

Riniker, Sereina ^{[2
]}

Marsault, Eric ^{[1
]}

机构：

[1] Univ Sherbrooke, Inst Pharmacol Sherbrooke, Dept Pharmacol Physiol, Sherbrooke, PQ 3001, Canada

[2] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland

[3] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 09期

基金：

瑞士国家科学基金会; 加拿大创新基金会; 加拿大自然科学与工程研究理事会;

关键词：

PROTEIN-PROTEIN INTERACTION; MOLECULAR-DYNAMICS; MEMBRANE-PERMEABILITY; ORAL BIOAVAILABILITY; CYCLIC-PEPTIDES; DRUG DISCOVERY; DATA SET; ABSORPTION; CACO-2; ISOMERIZATION;

D O I：

10.1021/acs.jmedchem.0c02036

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.

引用

页码：5365 / 5383

页数：19