SR8278 is a rev-erbα antagonist. It inhibits Rev-Erbα transcriptional repression (EC50 = 0.47 μM) and blocks activity of Rev-Erbα agonist GSK 4112 in HEK293 cells. SR8278 increases expression of glucose-regulating genes, G6Pase and PEPCK in HepG2 cells.
REV-ERBα is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBα suppresses transcription of its target genes in a heme-dependent manner. SR8278 displays REV-ERBα antagonist activity in contrast to the agonist activity displayed by GSK4112. Addition of SR8278 shows the opposite effect enhancing the expression of the reporter gene presumably due to blocking the action of the endogenous agonist heme. Addition of the antagonist, SR8278, results in inhibition of the REV-ERBα transcriptional repression activity in a dose-dependent manner (EC50=0.47μM). Treatment of HepG2 cells with 10 μM SR8278 for 24 h resulted in a significant increase in the expression of REV-ERBα target genes consistent with the compound blocking the action of the endogenous agonist, heme[1]. Specifically, the values of areas under plasma concentration time curves (AUC), initial plasma concentrations (C0), elimination half-lives (t1/2), and clearances (CL) were 608.33 ± 295.25 vs. 598.59 ± 276.92 ng·h/mL, 2410.25 ± 202.36 vs. 3742.11 ± 1300.21 ng/mL, 0.17 ± 0.08 vs. 0.11 ± 0.04 h, 3330.83 ± 1609.48 vs. 3364.81 ± 1111.38 mL/kg·h for SR8278 in normal rats vs. diabetic rats, respectively[2].
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