Département de Pharmacologie-Physiologie, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12e ave Nord, Sherbrooke, QC J1H5N4, Canada.
J Med Chem. 2024 Mar 14;67(5):3711-3726. doi: 10.1021/acs.jmedchem.3c02162. Epub 2024 Feb 28.
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 LiBH and the aqueous reductive mono--alkylation of aldehydes using catalytic SmI 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 ( 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.
大环化合物具有公认的治疗潜力，但它们的细胞通透性有限，这限制了它们作为口服药物的发展。为了更好地理解含杂环的半肽大环化合物的结构-通透性关系，我们合成了一个文库。这些化合物是通过开发本文所述的两个新反应来合成的：LiBH 还原活化肟和催化 SmI 和化学计量 Zn 还原醛的水相单烷基化。通过平行人工膜通透性测定 (PAMPA) 评估了大环化合物的通透性，结果表明，在结构中引入呋喃的大环化合物比具有吡咯部分的大环化合物具有更好的被动通透性。具有 2,5-取代吡咯（ 构象）的化合物被证明涉及分子内氢键，从而增强了它们的通透性。这项研究强调了杂环部分对半肽的影响，可形成高通透性的大环化合物，从而为药物的被动扩散提供了有前途的途径，超越了五规则化学空间。
