biostudies-literatureLy HMNatural Sciences and Engineering Research Council of CanadaUniversit? de SherbrookeProteo3711-3726https://www.ebi.ac.uk/biostudies/studies/S-EPMC10946398biostudies-literatureUnknown67(5)Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure-permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH₄ and the aqueous reductive mono-<i>N</i>-alkylation of aldehydes using catalytic SmI₂ and stoichiometric Zn. The permeability of the macrocycles was evaluated through a parallel artificial membrane permeability assay (PAMPA), and the results indicated that macrocycles with a furan incorporated into the structure have better passive permeability than those with a pyrrole moiety. Compounds bearing a 2,5-disubstituted pyrrole (<i>endo</i> orientation) were shown to be implicated in intramolecular H-bonds, enhancing their permeability. This study highlighted the impact of heterocycles moieties in semipeptides, creating highly permeable macrocycles, thus showing promising avenues for passive diffusion of drugs beyond the rule-of-five chemical space.Journal of medicinal chemistryInsights on Structure-Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles.PMC10946398RGPIN-2022-04028Desgagne MNguyen DTComeau CFroehlich UMarsault ELy HMBoudreault PLfalseInsights on Structure-Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles.Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure-permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH₄ and the aqueous reductive mono-<i>N</i>-alkylation of aldehydes using catalytic SmI₂ and stoichiometric Zn. The permeability of the macrocycles was evaluated through a parallel artificial membrane permeability assay (PAMPA), and the results indicated that macrocycles with a furan incorporated into the structure have better passive permeability than those with a pyrrole moiety. Compounds bearing a 2,5-disubstituted pyrrole (<i>endo</i> orientation) were shown to be implicated in intramolecular H-bonds, enhancing their permeability. This study highlighted the impact of heterocycles moieties in semipeptides, creating highly permeable macrocycles, thus showing promising avenues for passive diffusion of drugs beyond the rule-of-five chemical space.2024-01-01T00:00:00Z2024 Mar2025-04-03T23:36:28.918Z2025-04-03T23:36:28.918ZS-EPMC109463983841704010.1021/acs.jmedchem.3c02162