Diethylstilbestrol-scaffold-based pregnane X receptor modulators

Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroid...

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Veröffentlicht in:European journal of medicinal chemistry 2015-10, Vol.103, p.551-562
Hauptverfasser: Hodnik, Žiga, Tomašič, Tihomir, Smodiš, Domen, D'Amore, Claudio, Mašič, Lucija Peterlin, Fiorucci, Stefano, Kikelj, Danijel
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Sprache:eng
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Zusammenfassung:Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroids with PXR agonistic activity, solomonsterols A and B, and our recently reported bazedoxifene scaffold-derived PXR antagonists. The methylated diethylstilbestrol derivative 1 displayed potent PXR agonistic activity with an EC50 value of 10.5 μM, whereas compounds 3, 4 and 6 (IC50 for 6 = 27.4 μM) and diethylstilbestrol (2) itself (IC50 = 14.6 μM) exhibited PXR antagonistic effects in HepG2 cells. The PXR modulatory effects of the synthesized diethylstilbestrol derivatives were further confirmed by the induction of PXR-regulated CYP3A4 expression with compound 1, as well as by the inhibition of the rifaximin-promoted up-regulation of CYP3A4 expression with 2 and its derivative 6. [Display omitted] •A series of DES-based solomonsterol A and B analogs was synthesized.•The PXR modulatory activity of the compounds was evaluated.•The methylated DES derivative 1 showed PXR agonistic activity with EC50 of 10.5 μM.•DES and its analogs 3, 4 and 6 showed PXR antagonistic activity.•Compound 6 inhibited rifaximin-promoted up-regulation of CYP3A4 expression.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2015.09.005