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Abstract
Trisubstituted hydroxylamines are an underrepresented functional group in drug discovery and as such have lagged more traditional functional groups in terms of synthetic innovation. As presented in Chapter 2, the reaction of secondary amide nucleophiles with alcohol-derived 2-methyl-2-tetrahydropyranyl (MTHP) alkyl peroxides provides a convergent, scalable method for the synthesis of primary and secondary alcohol-derived N,N,O-trisubstituted hydroxylamines. Chapter 3 details the synthesis of O-tert-butyl-N,N-disubstituted hydroxylamines by reaction of secondary amide nucleophiles with the “sterically matched” tert-butyl 2,6-dimethyl-perbenzoate electrophile, thereby providing convergent approaches to primary, secondary, and tertiary derivatives of this underrepresented functional group.
Chapter 4 describes a matched molecular pair (MMP) analysis which indicates that replacement of isosteric alkane and ether moieties by trisubstituted hydroxylamines can decrease lipophilicity. On the other hand, the weakly basic but polar nature of trisubstituted hydroxylamines leads to increased logD7.4 values with respect to isosteric tertiary amines. It was also found that trisubstituted hydroxylamines can block metabolic soft spots including benzylic C-H centers and aryl amines to improve metabolic stability. Chapter 5 outlines the discovery efforts culminating in a highly selective, brain penetrant epidermal growth factor receptor (EGFR) inhibitor bearing a trisubstituted hydroxylamine as a key structural motif. In an intracranial patient-derived xenograft (PDX) murine model, oral dosing with the optimal compound leads to profound tumor regression, suggesting it as a candidate for treatment of EGFR+ non-small-cell lung cancer (NSCLC). Contrary to the common expectation for hydroxylamines, the lead compound is not mutagenic, genotoxic or acutely toxic in vivo at the tested doses.
Chapter 6 illustrates the N-alkyl to N-noralkoxy switch applied to a dual proto-oncogene tyrosine-protein kinase Src (cSRC) breakpoint cluster region – Abelson proto-oncogene 1 (BCR-ABL1) inhibitor, bosutinib. The bioisosteric switch leads to reduced drug efflux and hERG affinity at the expense of an insignificant 2 amu increase in molecular weight. The optimal compound also critically lacks both mutagenicity and genotoxicity and retains high oral bioavailability in vivo without evidence of acute toxicity at the tested doses. A MMP analysis suggests that the benefits conferred by the N-alkyl to N-noralkoxy switch arise from a reduction in pKa about the basic piperazine heterocycle.
Chapter 4 describes a matched molecular pair (MMP) analysis which indicates that replacement of isosteric alkane and ether moieties by trisubstituted hydroxylamines can decrease lipophilicity. On the other hand, the weakly basic but polar nature of trisubstituted hydroxylamines leads to increased logD7.4 values with respect to isosteric tertiary amines. It was also found that trisubstituted hydroxylamines can block metabolic soft spots including benzylic C-H centers and aryl amines to improve metabolic stability. Chapter 5 outlines the discovery efforts culminating in a highly selective, brain penetrant epidermal growth factor receptor (EGFR) inhibitor bearing a trisubstituted hydroxylamine as a key structural motif. In an intracranial patient-derived xenograft (PDX) murine model, oral dosing with the optimal compound leads to profound tumor regression, suggesting it as a candidate for treatment of EGFR+ non-small-cell lung cancer (NSCLC). Contrary to the common expectation for hydroxylamines, the lead compound is not mutagenic, genotoxic or acutely toxic in vivo at the tested doses.
Chapter 6 illustrates the N-alkyl to N-noralkoxy switch applied to a dual proto-oncogene tyrosine-protein kinase Src (cSRC) breakpoint cluster region – Abelson proto-oncogene 1 (BCR-ABL1) inhibitor, bosutinib. The bioisosteric switch leads to reduced drug efflux and hERG affinity at the expense of an insignificant 2 amu increase in molecular weight. The optimal compound also critically lacks both mutagenicity and genotoxicity and retains high oral bioavailability in vivo without evidence of acute toxicity at the tested doses. A MMP analysis suggests that the benefits conferred by the N-alkyl to N-noralkoxy switch arise from a reduction in pKa about the basic piperazine heterocycle.