DDO-7263

DDO-7263 is an activator of the Nrf2-ARE pathway.¹ It induces Nrf2-mediated transcription in a reporter assay using HepG2 cells expressing the antioxidant response element (ARE) at 0.01-80 µM.² DDO-7263 binds to the 26S proteasome regulatory subunit RPN6 and prevents proteasomal degradation of ubiquitinated Nrf2.¹ It reduces cell death induced by acetaminophen (Item No. 10024) in L-02 hepatocytes at 5-20 µM and reduces acetaminophen-induced liver injury in mice at 50-100 mg/kg.² DDO-7263 also reduces dopaminergic cell death in the substantia nigra and striatum and improves motor activity in a mouse model of MPTP-induced Parkinson’s disease.³

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1. Dai, Z., An, L., Chen, X., et al. Target fishing reveals a novel mechanism of 1,2,4-oxadiazole derivatives targeting Rpn6, a subunit of 26S proteasome. J. Med. Chem. 65(6), 5029-5043 (2022).

2. Xu, L.L., Wu, Y.F., Wang, L., et al. Structure-activity and structure-property relationships of novel Nrf2 activators with a 1,2,4-oxadiazole core and their therapeutic effects on acetaminophen (APAP)-induced acute liver injury. Eur. J. Med. Chem. 157, 1376-1394 (2018).

3. Xu, L.L., Wu, Y.F., Yan, F., et al. 5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson’s disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress. Free Radic. Biol. Med. 134, 288-303 (2019).