title: Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human constitutive androstane receptor.
abstract: The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor responsible for the recognition of potentially toxic endo- and exogenous compounds whose elimination from the body is accelerated by the CAR-mediated inducible expression of metabolizing enzymes and transporters. Despite the importance of CAR, few human agonists are known so far. Following a sequential virtual screening procedure using a 3D pharmacophore and molecular docking approach, we identified 17 novel agonists that could activate human CAR in vitro and enhance its association with the nuclear receptor co-activator SRC1. Selected agonists also increased the expression of the human CAR target CYP2B6 mRNA in primary hepatocytes. Composed of substituted sulfonamides and thiazolidin-4-one derivatives, these agonists represent two novel chemotypes capable of human CAR activation, thus broadening the agonist spectrum of CAR.
authors.affiliation: Department of Pharmaceutics, University of Kuopio, Yliopistonranta 1C, FI-70210 Kuopio, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Küblbeck
authors.forename: Johanna
authors.initials: J
authors.lastname: Jyrkkärinne
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
mesh_terms: D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D053778:Thiazolidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D053778:Thiazolidines; D014157:Transcription Factors