Reducing the Lipophilicity of Perfluoroalkyl Groups by CF2-F/CF2-Me or CF3/CH3 Exchange
Reducing the Lipophilicity of Perfluoroalkyl Groups by CF2-F/CF2-Me or CF3/CH3 Exchange
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DOI：
10.1021/acs.jmedchem.8b01222
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发表时间：
2018-12-13
影响因子：
7.3
通讯作者：
Linclau, Bruno
中科院分区：
文献类型：
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作者：
Jeffries, Benjamin;Wang, Zhong;Linclau, Bruno
氟化通常用于优化候选药物的生物活性和药效动力学性质。脂肪族烃通常降低亲脂性（log P），但多氟烷基化通常增加亲脂性。因此，鉴定仍然导致相似或甚至降低的亲脂性的多氟化基序对于扩大药物化学工具库以解决诸如化合物代谢稳定性或脱靶选择性的性质是有意义的。我们表明，改变CF 3-基团的全氟烷基链的甲基基团导致亲油性急剧减少。我们还表明，改变三氟甲基基团的C-F键，包括当作为全氟烷基基团的一部分并入时，改变为C-Me基团，导致log P降低，尽管导致链延长。在氟化烷醇模型中鉴定了所观察到的亲脂性趋势，并在掺入候选药物的类似物中时重现，并证明了这些基序的代谢稳定性。
Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF3-group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C-F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C-Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.