Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human constitutive androstane receptor.
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.
Küblbeck
Jenni
J
Department of Pharmaceutics, University of Kuopio, Yliopistonranta 1C, FI-70210 Kuopio, Finland.
Jyrkkärinne
Johanna
J
Poso
Antti
A
Turpeinen
Miia
M
Sippl
Wolfgang
W
Honkakoski
Paavo
P
Windshügel
Björn
B
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*
D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D053778:Thiazolidines; D014157:Transcription Factors