SR9238 is a selective inverse agonist of LXRα and LXRβ with IC50 values of 214 and 43 nM, respectively [1].
The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily that act as ligand-dependent transcription factors. LXRα is mainly expressed in the liver, kidneys, intestines, and adipose tissues while LXRβ is ubiquitously expressed. LXRs are well-characterized regulators of the expression of an array of lipogenic enzyme genes [1][2].
SR9238 is a potent and selective inverse agonist of LXRα and LXRβ. SR9238 increased interaction of corepressor NCoR ID1 with LXRα and LXRβ with EC50 values of 33 nM and 13 nM, respectively, and NCoR ID2 with LXRα and LXRβ with EC50 values of >10 μM and 93 nM. SR9238 also effectively inhibited transcription from a Fasn promoter driven luciferase reporter [1].
In mice, SR9238 was detected in the liver 2h after the injection and was not detectable in the plasma, skeletal muscle or brain. SR9238 displayed liver specific exposure. In hepatic steatosis mice, SR9238 (30 mg/kg/day, i.p.) significantly inhibited lipogenic gene expression and reduced lipid content in the liver [1]. In non-alcoholic steatohepatitis mice, SR9238 significantly reduced the severity of hepatic steatosis, reduced hepatic inflammation and ameliorated hepatic fibrosis [2].
References:
[1]. Griffett K, Solt LA, El-Gendy Bel-D, et al. A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013 Mar 15;8(3):559-67.
[2]. Griffett K, Welch RD, Flaveny CA, et al. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol Metab. 2015 Feb 9;4(4):353-7.