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

Abstract

The influence of substitution of an N,N,O-trisubstituted hydroxylamine (−NR−OR′−) unit for a hydrocarbon (−CHR− CH 2 −), 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 logD 7.4 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.

Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer

“…Spectral data are in accord with that previously reported in the literature. 47 TLC R f = 0.50 (20:80 EtOAc/Hexanes; CAM). 1 H NMR (500 MHz, CDCl 3 ) δ 4.13−4.07 (m, 2H), 3.92 (td, J = 11.4, 2.8 Hz, 1H), 3.85 (t, J = 5.4 Hz, 2H), 3.71−3.68 (m, 1H), 1.79−1.50 (m, 6H), 1.43 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H).…”

Recent Advances in the Synthesis of Di- and Trisubstituted Hydroxylamines

“…Compared to O -acyl- N , N -disubstituted hydroxylamines and related derivatives, the chemistry of di- and trialkylhydroxylamines is much less studied. With experimentally determined bond dissociation energy (BDE) values from 55 to 65 kcal·mol −1 a pKa of 5.93 in aqueous solution for the conjugate acid of hydroxylamine itself, and barriers to stereomutation, nitrogen inversion, or N-O bond rotation of approximately 15 kcal·mol −1 , the di- and trialkylhydroxylamine units offer interesting properties situated in unique chemical space [ 11 , 12 , 13 , 14 , 15 , 16 ]. The trialkylhydroxylamine unit is found in approved scaffolds such as the anti-insecticidal spiropidion, developed by Syngenta, the tetracycline-derived antibiotic sarecycline, developed by Allergen (acquired by Almirall), and has been used as a phosphate replacement in nucleotide analogs by Alnylam, but such examples are rare ( Figure 1 B) [ 17 , 18 , 19 ].…”

Atypical N-Alkyl to N-Noralkoxy Switch in a Dual cSRC/BCR-ABL1 Kinase Inhibitor Improves Drug Efflux and hERG Affinity

“…While bosutinib, dasatinib, and asciminib have lower affinity for the hERG ion channel, these second- and third- generation BCR-ABL1 inhibitors are substrates for efflux transporters P-gp and/or BCRP, which can confer indirect inhibitor resistance through active drug efflux. − Thus, developing potent inhibitors of BCR-ABL1 with minimal affinity for the hERG ion channel and reduced drug efflux is of significant interest for the clinical management of Ph+ CML. Building on our previous results, we hypothesized that a bioisosteric replacement of the N -alkyl piperazine unit in bosutinib by an equivalent hydroxylamine N -noralkoxy unit would attenuate the basicity and modify the lipophilicity of bosutinib to reduce hERG affinity and efflux propensity (Figure c). Herein, we reduce this hypothesis to practice and report on the direct incorporation of a trisubstituted hydroxylamine N -noralkoxy unit into a bosutinib N -alkyl unit that leads to both a reduction in hERG affinity and efflux propensity at the expense of an insignificant molecular weight increase of 2 atomic mass units (amu).…”

“…1−3 Unlike lesser substituted hydroxylamines 4,5 and structurally related hydroxamates, 6,7 which confer mutagenicity by metabolic activation to electrophilic nitroso derivatives or isocyanates and subsequent conjugation with DNA, 2 exhibited good stability in vitro and in vivo and critically lacked both mutagenicity and genotoxicity. 8,9 We now describe the extension of this novel bioisosteric design strategy to the FDA-approved small molecule drug, bosutinib (3).…”

“…We recently described compound 2 , a hydroxylamine-bearing, orally bioavailable, brain-penetrant, selective epidermal growth factor receptor (EGFR) inhibitor with potential for treating EGFR+ central nervous system (CNS) metastases in non-small-cell lung cancer (NSCLC) (Figure a) . Key to the discovery of 2 was the recognition that derivatization of a saturated nitrogen heterocycle in the form of a hydroxylamine could attenuate basicity and modify the lipophilicity of the starting molecule, gefitinib ( 1 ), in such a way that 2 evades efflux by transporters, such as P-glycoprotein (P-gp, or MDR1), and/or breast cancer resistance protein (BCRP). − Unlike lesser substituted hydroxylamines , and structurally related hydroxamates, , which confer mutagenicity by metabolic activation to electrophilic nitroso derivatives or isocyanates and subsequent conjugation with DNA, 2 exhibited good stability in vitro and in vivo and critically lacked both mutagenicity and genotoxicity. , We now describe the extension of this novel bioisosteric design strategy to the FDA-approved small molecule drug, bosutinib ( 3 ).…”