The N,N,O-Trisubstituted Hydroxylamine Isostere and Its Influence on Lipophilicity and Related Parameters

The influence of substitution of an N,N,O-trisubstituted hydroxylamine (−NR–OR′−) unit for a hydrocarbon (−CHR–CH2−), 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 N,N,O-trisubstituted hydroxylamines typically leads to a reduction in logP comparable to that achieved with a tertiary amine group. In contrast, the weakly basic N,N,O-trisubstituted hydroxylamines have greater logD7.4 values than tertiary amines. It is also demonstrated that the N,N,O-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 N,N,O-trisubstituted hydroxylamine moiety in small-molecule optimization schemes in medicinal chemistry.