This is a proposal to develop new tools for the practical effective synthesis of N,N,O-
trisubstituted hydroxylamines, or hydroxalogs, as novel isosteres for application in
medicinal chemistry across a broad swath of compound classes and diseases states.
The three specific aims presented encompass i) tools development for the synthesis of
N,N,O-trisubstituted hydroxylamines by a variety of inter- and intramolecular methods; ii)
synthesis of a series of phenylpropylpiperidine ligands for the s-1 and s-2 receptors and
their use as models for the comparative study of the physical and drug-like properties of
the hydroxalogs, thereby enhancing their applicability as tools in medicinal chemistry; iii)
synthesis of a series of hydroxalogs of the ethanolamine H1 antagonists and
comparative determination of their antihistamine activity in a cell-based assay, again
with the view to validating the hydroxalogs as isosteres as tools in medicinal chemistry.