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

Abstract

We describe an atypical amine bioisostere, the trisubstituted hydroxylamine, that upon incorporation into an approved dual cSRC/BCR-ABL1 kinase inhibitor yields 9 , a compound that retains potent biological activity and couples it with improved drug efflux and hERG affinity at the expense of only a 2 atomic mass unit increase in molecular weight. Contrary to the common expectation for hydroxylamines in medicinal chemistry, 9 is well tolerated in vivo and lacks the mutagenicity and genotoxicity so often ascribed to lesser substituted hydroxylamines. A matched molecular pair (MMP) analysis suggests that the beneficial properties conferred by the N -alkyl to N -noralkoxy switch arises from a reduction in basicity of the piperazine unit. Overall, these results lend additional support to the use of trisubstituted hydroxylamines as bioisosteres of N -alkyl groups that are not involved in key polar interactions.