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  • Bazedoxifene scaffold-based mimetics of solomonsterols A and B as novel pregnane X receptor antagonists
    Hodnik, Žiga, farmacevt ...
    Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug metabolising enzymes and transporters. The ... overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multi drug resistance in anticancer treatments. We describe the discovery of novel, bazedoxifene scaffold-based PXR antagonists, inspired by the marine sulphated steroids, solomonsterols A and B, as natural leads. Luciferase reporter assay on a PXR transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship study of the most active PXR antagonist from the series (compound 20, IC50 = 11 [micro]M revealed the importance of hydroxy groups as hydrogen bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 [micro]M), in addition to the down-regulation of PXR expression, exhibited an inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase I drug metabolism.
    Vir: Journal of medicinal chemistry. - ISSN 0022-2623 (Vol. 57, no. 11, 2014, str. 4819-4833)
    Vrsta gradiva - članek, sestavni del
    Leto - 2014
    Jezik - angleški
    COBISS.SI-ID - 3647601

    Povezava(-e):

    http://pubs.acs.org/doi/abs/10.1021/jm500351m
    DOI

vir: Journal of medicinal chemistry. - ISSN 0022-2623 (Vol. 57, no. 11, 2014, str. 4819-4833)
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