2‑(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists

Constitutive
androstane receptor (CAR) is a key regulator of xenobiotic
and endobiotic metabolism. Together with pregnane X (PXR) and aryl
hydrocarbon (AHR) receptors, it is referred to as “xenobiotic
receptor”. The unique properties of human CAR, such as its
high constitutive activity, both direct (ligand-binding domain-dependent)
and indirect activation have hindered the discovery of direct selective
human CAR ligands. Herein, we report a novel class of direct human
CAR agonists in a group of 2-(3-methoxyphenyl)­quinazoline derivatives.
The compounds are even more potent activators of human CAR than is
prototype 6-(4-chlorophenyl)­imidazo­[2,1-b]­[1,3]­thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)­oxime (CITCO). The three most potent
ligands are at the same time extremely potent activators of the other
xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor,
which regulate major xenobiotic-metabolizing enzymes and efflux transporters.
Thus, the novel CAR ligands can be also considered as constituting
the first class of potent pan-xenobiotic receptor ligands that can
serve as potential antidotes boosting overall metabolic elimination
of xenobiotic or toxic compounds.