Structure–Property Relationship Analysis of α-Keto Ester Prodrugs of Monomethyl Fumarate as NRF2 Activators

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of the antioxidant response pathway and an attractive target for treating diseases driven by oxidative stress, such as peripheral neuropathy. While activation of NRF2 by monomethyl fumarate (MMF) is well established, the systemic exposure and broad side-effect profile of MMF and its two FDA-approved prodrugs, diroximel fumarate and dimethyl fumarate, limit their broader therapeutic utility. To address this limitation, we present a series of α-keto ester-functionalized prodrugs of MMF (1-21), designed to release therapeutically active MMF selectively at the site of oxidative stress. These prodrugs were designed to exploit elevated pathological levels of reactive oxygen species (ROS), which trigger Baeyer-Villiger oxidation of the α-keto ester moiety, resulting in rapid hydrolysis of the generated anhydride and localized MMF release. Multiple α-keto esters (1-11, 13-16, and 18-21) demonstrated activity relative to MMF in our in vitro NRF2 reporter cell assay, but only in the presence of H2O2. Furthermore, structure-property relationship (SPR) analysis revealed that prodrugs with simple alkyl α-keto esters demonstrated the highest levels of NRF2 activation and therapeutic efficacy. Specifically, α-keto esters 4, 5, and 6, functionalized with trideutero methyl, ethyl, and iso-propyl esters, respectively, exhibit strong tissue-specific NRF2 activation in vivo, where 4 demonstrated full reversal of mechanical allodynia in a mouse model of neuropathy. These findings firmly establish α-keto ester prodrugs of MMF as a next-generation NRF2-targeting modality that overcomes the systemic exposure and off-target liabilities of existing fumarate therapies by exploiting pathological ROS as a trigger.