title: 2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists.
abstract: 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.
authors.forename: Tomas
authors.initials: T
authors.lastname: Smutny
authors.affiliation: Institute of Molecular and Translation Medicine, Faculty of Medicine, Palacky University in Olomouc , Hnevotinska 5, CZ-779 00 Olomouc, Czech Republic.
authors.forename: Alice
authors.initials: A
authors.lastname: Nova
authors.forename: Marcela
authors.initials: M
authors.lastname: Drechslerová
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carazo
authors.forename: Lucie
authors.initials: L
authors.lastname: Hyrsova
authors.forename: Zuzana Rania
authors.initials: ZR
authors.lastname: Hrušková
authors.forename: Jiří
authors.initials: J
authors.lastname: Kuneš
authors.forename: Milan
authors.initials: M
authors.lastname: Pour
authors.forename: Marcel
authors.initials: M
authors.lastname: Špulák
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
mesh_terms: D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000090702:Constitutive Androstane Receptor; D004791:Enzyme Inhibitors; D011799:Quinazolines; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System