Bazedoxifene-Scaffold-Based Mimetics of Solomonsterols A and B as Novel Pregnane X Receptor Antagonists

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• 作者：沤iga Hodnik ; Lucija Peterlin Ma拧i膷 ; Tihomir Toma拧i膰 ; Domen Smodi拧 ; Claudio D鈥橝more ; Stefano Fiorucci ; Danijel Kikelj
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4819-4833
• 全文大小：589K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19鈥?b>24 as promising PXR antagonists. Further structure鈥揳ctivity relationship studies of the most active PXR antagonist from the series (compound 20, IC₅₀ = 11 渭M) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC₅₀ = 14 渭M), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism.