Building a Chemical Toolbox for Human Pregnane X Receptor Research: Discovery of Agonists, Inverse Agonists, and Antagonists Among Analogs Based on the Unique Chemical Scaffold of SPA70

Pregnane
X receptor (PXR) plays roles in detoxification and other
physiological processes. PXR activation may enhance drug metabolism
(leading to adverse drug reactions) or inhibit inflammation. Therefore,
PXR agonists, antagonists, and inverse agonists may serve as research
tools and drug candidates. However, a specific PXR modulator with
an associated structure–activity relationship is lacking. Based
on the scaffold of specific human PXR (hPXR) antagonist SPA70 (10), we developed 81 SPA70 analogs and evaluated their receptor-binding
and cellular activities. Interestingly, analogs with subtle structural
differences displayed divergent cellular activities, including agonistic,
dual inverse agonistic and antagonistic, antagonistic, and partial
agonistic/partial antagonistic activities (as in compounds 111, 10, 97, and 42, respectively).
We generated a pharmacophore model that represents 81 SPA70 analogs,
and docking models that correlate strong interactions between the
compounds and residues in the AF-2 helix with agonistic activity.
These compounds are novel chemical tools for studying hPXR.