New opportunities for pregnane X receptor (PXR) targeting in drug development. lessons from Enantio- and species-specific PXR ligands identified from a discovery library of amino acid analogues.

Nuclear hormone receptors (NHRs) are transcription factors that bind to lipophilic signaling molecules (ligands), and subsequently regulate the expression of target genes. Since NHR ligands have potential as therapeutic agents, one of the most active research areas in the NHR field is the synthesis and identification of small molecule ligands for NHRs. Wipf et al. have recently reported the creation of a discovery library using a new method for the synthesis of homoallylic amides, allylic amides and C-cyclopropylalkylamides. This article is intended to review the use of this discovery library to screen for activators for the pregnane X receptor (PXR), a master xenobiotic receptor that regulates the expression of Phase I and Phase II enzymes as well as drug transporters. Our screening of the discovery library identified potent PXR activators whose carbon scaffolds are distinct from the chemical structures of known PXR agonists. Moreover, we found that enantiomers of the same compound show a species-specific activation of PXR. The development of the discovery library and the implications of enantiospecificity of PXR ligand design represent the primary focus of this account.