Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

Zuercher, William J.; Buckholz, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M.

doi:10.1021/jm901797p

Cited by 80 publications

(64 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A) as an LXR antagonist that displayed high binding affinity for LXR while antagonizing LXR target gene expression in cell culture [21]. We confirmed this activity in cell based cotransfection assays where we assessed the ability of GSK2033 to suppress basal transcription LXRα and LXRβ as detected by luciferase reporters driven by either DR4 LXREs (Fig.…”

Section: Resultsmentioning

confidence: 54%

“…Here, we assessed the effects of GSK2033 in the identical mouse model of NAFLD. GSK2033 is described as a LXR antagonist [21] although we observed clear inverse agonist activity as well. GSK2033 display systemic exposure and we believed it might be a good comparison to SR9238, which displays liver specificity.…”

Section: Discussionmentioning

confidence: 58%

“…SR9238 displays efficacy in reducing fatty liver in a mouse model of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis [24,25]. In this study, we examined the activity of a LXR antagonist that displays systemic exposure, GSK2033 [21]. …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease

Griffett

Burris

2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The liver X receptor (LXR) functions as a receptor for oxysterols and plays a critical role in the regulation of glucose and lipid metabolism. We recently described a synthetic LXR inverse agonist that displayed efficacy in treatment of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). This compound, SR9238, was designed to display liver specificity so as to avoid potential detrimental effects on reverse cholesterol transport in peripheral tissues. Here, we examined the effects of a LXR antagonist/inverse agonist, GSK2033, which displays systemic exposure. Although GSK2033 performed as expected in cell-based models as a LXR inverse agonist, it displayed unexpected activity in the mouse NAFLD model. The expression of lipogenic enzyme genes such as fatty acid synthase and sterol regulatory binding protein 1c were induced rather than suppressed and no effect on hepatic steatosis was found. Further characterization of the specificity of GSK2033 revealed that it displayed a significant degree of promiscuity, targeting a number of other nuclear receptors that could clearly alter hepatic gene expression.

show abstract

Section: Resultsmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 58%

See 1 more Smart Citation

Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease

Griffett

Burris

2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…30 Detailed SAR studies indicated that the position of the morpholinosulfonyl moiety of the F2 phenyl ring is important to modifications (Tables 1 and 2). Further analysis of the essential structural requirements for effective FXR antagonists showed that the meta-position-substituted morpholinosulfonyl moiety on the aniline amide moiety would influence the antagonistic activity.…”

Section: Resultsmentioning

confidence: 99%

Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Lin

Forman

et al. 2014

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR.

show abstract

“…Although the LXR-deficient macrophages had higher basal levels of ABCA1, as previously reported (36), incubation with apoptotic cells significantly increased ABCA1 transcript levels in the Lxra/b -/-macrophages ( Figure 3B). In contrast, the Lxra/b -/-macrophages were completely deficient in increasing the Abca1 message in response to the LXR agonist TO-901317 (denoted 1317) ( Figure 3C) (37).…”

Section: Apoptotic Cells Induce a Transcriptional Upregulation Of Abca1mentioning

confidence: 98%

Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1

Fond¹,

Lee²,

Schulman³

et al. 2015

J. Clin. Invest.

View full text Add to dashboard Cite

Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

Cited by 80 publications

References 17 publications

Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease

Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease

Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1

Contact Info

Product

Resources

About