SR 12813 - CAS 126411-39-0
Category: Inhibitor
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Molecular Weight:
HMG-CoA Reductase (HMGCR)
SR 12813 is a pregnane X receptor (PXR) agonist (EC50 = 200 and 700 nM for human and rabbit PXR, respectively) that activates the farnesoid X receptor (FXR) at μM concentrations. SR 12813 exhibits hypocholesterolaemic activity via enhancing the degradation of HMG-CoA reductase.
Brife Description:
PXR agonist
≥99% by HPLC
SR 12813; SR12813; SR-12813; [[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester; 4-[2,2-bis(diethoxyphosphoryl)ethenyl]-2,6-ditert-butylphenol
Canonical SMILES:
1.The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
Watkins RE;Wisely GB;Moore LB;Collins JL;Lambert MH;Williams SP;Willson TM;Kliewer SA;Redinbo MR Science. 2001 Jun 22;292(5525):2329-33. Epub 2001 Jun 14.
The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.
2.BFCOD activity in fish cell lines and zebrafish embryos and its modulation by chemical ligands of human aryl hydrocarbon and nuclear receptors.
Creusot N;Brion F;Piccini B;Budzinski H;Porcher JM;Aït-Aïssa S Environ Sci Pollut Res Int. 2015 Nov;22(21):16393-404. doi: 10.1007/s11356-014-3882-8. Epub 2014 Dec 4.
Assessment of exposure and effect of fish to pharmaceuticals that contaminate aquatic environment is a current major issue in ecotoxicology and there is a need to develop specific biological marker to achieve this goal. Benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylase (BFCOD) enzymatic activity has been commonly used to monitor CYP3A activity in fish. In this study, we assessed the capacity of a panel of toxicologically relevant chemicals to modulate BFCOD activity in fish, by using in vitro and in vivo bioassays based on fish liver cell lines (PLHC-1, ZFL, RTL-W1) and zebrafish embryos, respectively. Basal BFCOD activity was detectable in all biological models and was differently modulated by chemicals. Ligands of human androgens, glucocorticoids, or pregnanes X receptors (i.e., dexamethasone, RU486, rifampicin, SR12813, T0901317, clotrimazole, ketoconazole, testosterone, and dihydrotestosterone) moderately increased or inhibited BFCOD activity, with some variations between the models. No common feature could be drawn by regards to their capacity to bind to these receptors, which contrasts with their known effect on mammalian CYP3A. In contrast, dioxins and polycyclic aromatic hydrocarbons (PAHs) strongly induced BFCOD activity (up to 30-fold) in a time- and concentration-dependent manner, both in vitro in all cell lines and in vivo in zebrafish embryos.
3.Statins Attenuate Activation of the NLRP3 Inflammasome by Oxidized LDL or TNF
Wang S;Xie X;Lei T;Zhang K;Lai B;Zhang Z;Guan Y;Mao G;Xiao L;Wang N Mol Pharmacol. 2017 Sep;92(3):256-264. doi: 10.1124/mol.116.108100. Epub 2017 May 25.
Excessive activation of the NLRP3 inflammasome is implicated in cardiovascular diseases. Statins exert an anti-inflammatory effect independent of their cholesterol-lowering effect. This study investigated the potential role of statins in the activation of the NLRP3 inflammasome in endothelial cells (ECs). Western blotting and quantitative reverse-transcription polymerase chain reaction showed that oxidized low-density lipoprotein (ox-LDL) or tumor necrosis factor α (TNF;α;) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of ox-LDL or TNF;α; Promoter reporter assays and small interfering RNA knockdown revealed that statins inhibit ox-LDL-mediated NLRP3 inflammasome activation via the pregnane X receptor (PXR). In addition, PXR agonists (rifampicin and SR12813) or overexpression of a constitutively active PXR markedly suppressed the NLRP3 inflammasome activation. Conversely, PXR knockdown abrogated the suppressive effect of rifampicin on NLRP3 inflammasome activation. Knockdown of lectin-like ox-LDL receptor or overexpression of I;κ;B;α;-attenuated ox-LDL- or TNF;α;-triggered activation of the NLRP3 inflammasome. Chromatin immunoprecipitation assays indicated that mevastatin inhibited nuclear factor-κB binding to the promoter regions of the human NLRP3 gene.
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CAS 126411-39-0 SR 12813

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