E6446 dihydrochloride, a powerful and orally active antagonist of TLR7 and TLR9, is utilized in studying harmful inflammatory responses. Additionally, it acts as a potent inhibitor of SCD1 (KD: 4.61 μM), effectively reducing adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. E6446 dihydrochloride also ameliorates liver pathology in mice fed a high-fat diet (HFD), suggesting its potential utility in researching non-alcoholic fatty liver disease (NAFLD)[1][2][3].
体内研究
E6446 (20, 60 mg/kg, pO.) progressively reduces TLR9 signaling in mice.E6446 (60, 120 mg/kg, pO.) mitigates TLR hyperresponsiveness and LPS-induced septic shock in rodent malaria, lowers TLR reactivity in acute malaria, and curtails the activation of both TLR7 and TLR9[2].
体外研究
E6446 dihydrochloride functions as a strong, orally active inhibitor of TLR7 and TLR9. It effectively diminishes DNA-induced activation of HEK:TLR9 cells with an IC50 of 10 nM, yet shows considerably less efficacy in reducing LPS endotoxin-induced activation of HEK:TLR4 cells or R848-induced activation of HEK:TLR7 cells. E6446 robustly reduces IL-6 production triggered by CpG2216 but does not affect IL-6 production initiated by the TLR3 ligand poly inosine-cytosine. The capacity of E6446 to inhibit TLR7 varies according to the ligand, being a strong inhibitor of IL-6 production by RNA but a less effective inhibitor of IL-6 production by the small molecule imidazoquinoline ligand R-848. E6446 also inhibits TLR9-DNA interaction in vitro, with an IC50 ranging from 1 to 10 μM[1].
E6446 (0.01-0.03 μM) specifically blocks TLR9 activation by CpG ODN 2006 and inhibits TLR7/8 activation by the imidazoquinoline compound R848 at concentrations of 2-8 μM. It decreases TLR4 activation by 50% at a concentration of 30 μM, demonstrating IC50 values of 0.01 μM in HEK-TLR9 cells activated with oligo 2006 and 0.23 μM in human PBMCs activated with oligo 2216, respectively[2].
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