title: New in vitro tools to study human constitutive androstane receptor (CAR) biology: discovery and comparison of human CAR inverse agonists.
abstract: The human constitutive androstane receptor (CAR, NR1I3) is one of the key regulators of xenobiotic and endobiotic metabolism. The unique properties of human CAR, such as the high constitutive activity and the complexity of signaling, as well as the lack of functional and predictive cell-based assays to study the properties of the receptor, have hindered the discovery of selective human CAR ligands. Here we report a novel human CAR inverse agonist, 1-[(2-methylbenzofuran-3-yl)methyl]-3-(thiophen-2-ylmethyl) urea (S07662), which suppresses human CAR activity, recruits the corepressor NCoR in cell-based assays, and attenuates the phenytoin- and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO)-induced expression of CYP2B6 mRNA in human primary hepatocytes. The properties of S07662 are also compared with those of known human CAR inverse agonists by using an array of different in vitro and in silico assays. The identified compound S07662 can be used as a chemical tool to study the biological functions of human CAR and also as a starting point for the development of new drugs for various conditions involving the receptor.
authors: Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland & Biocenter Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland. jenni.kublbeck@uef.fi
authors: Jenni
authors: J
authors: Küblbeck
authors: Johanna
authors: J
authors: Jyrkkärinne
authors: Ferdinand
authors: F
authors: Molnár
authors: Tiina
authors: T
authors: Kuningas
authors: Jayendra
authors: J
authors: Patel
authors: Björn
authors: B
authors: Windshügel
authors: Tapio
authors: T
authors: Nevalainen
authors: Tuomo
authors: T
authors: Laitinen
authors: Wolfgang
authors: W
authors: Sippl
authors: Antti
authors: A
authors: Poso
authors: Paavo
authors: P
authors: Honkakoski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D000090702:Constitutive Androstane Receptor; D055808:Drug Discovery; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry; D008782:Methylurea Compounds / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013876:Thiophenes / Q000737:chemistry*
chemical_list: C572052:1-((2-methylbenzofuran-3-yl)methyl)-3-(thiophen-2-ylmethyl)urea; D000970:Antineoplastic Agents; D000090702:Constitutive Androstane Receptor; D007546:Isoquinolines; D008782:Methylurea Compounds; C000716327:NR1I3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D013876:Thiophenes; C037850:PK 11195