Hill Jarvis, Crich David
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602, United States.
Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, Georgia 30602, United States.
ACS Med Chem Lett. 2022 Apr 20;13(5):799-806. doi: 10.1021/acsmedchemlett.1c00713. eCollection 2022 May 12.
The influence of substitution of an -trisubstituted hydroxylamine (-NR-OR'-) unit for a hydrocarbon (-CHR-CH-), ether (-CHR-OR'-), or amine (-NR-CHR'-) moiety on lipophilicity and other ADME parameters is described. A matched molecular pair analysis was conducted across five series of compounds, which showed that the replacement of carbon-carbon bonds by -trisubstituted hydroxylamines typically leads to a reduction in log comparable to that achieved with a tertiary amine group. In contrast, the weakly basic -trisubstituted hydroxylamines have greater log values than tertiary amines. It is also demonstrated that the -trisubstituted hydroxylamine moiety can improve metabolic stability and reduce human plasma protein binding relative to the corresponding hydrocarbon and ether units. Coupled with recent synthetic methods for hydroxylamine assembly by N-O bond formation, these results provide support for the re-evaluation of the -trisubstituted hydroxylamine moiety in small-molecule optimization schemes in medicinal chemistry.
描述了用 - 三取代羟胺（-NR-OR'）单元取代烃基（-CHR-CH-）、醚基（-CHR-OR'）或胺基（-NR-CHR'）部分对亲脂性和其他药代动力学参数的影响。对五个系列的化合物进行了匹配分子对分析，结果表明，用 - 三取代羟胺取代碳 - 碳键通常会导致log值降低，其程度与叔胺基团取代时相当。相比之下，弱碱性的 - 三取代羟胺的log值比叔胺更大。还证明，相对于相应的烃基和醚基单元，- 三取代羟胺部分可以提高代谢稳定性并降低人血浆蛋白结合率。结合最近通过N - O键形成组装羟胺的合成方法，这些结果为在药物化学小分子优化方案中重新评估 - 三取代羟胺部分提供了支持。
