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 and an attractive target for treating diseases driven by oxidative stress, particularly neuropathy. While activation of NRF2 by monomethyl fumarate (MMF) is well established in rodent models, this mechanism is not confirmed as the primary mode of action in its approved use for relapsing-remitting multiple sclerosis (RRMS). Nevertheless, the systemic exposure and broad side-effect profile of MMF and its two FDA approved prodrugs, Vumerity and Tecfidera, limit broader therapeutic utility. These side effects may be acceptable in debilitating neurodegenerative disorders, such as RRMS, but are not for other indications, such as neuropathic pain. Here, we report the synthesis, in vitro and in vivo evaluation of a series of α-keto ester-functionalized prodrugs of MMF (1–23), designed to release the therapeutically active MMF selectively at sites of oxidative stress. These prodrugs were designed to exploit elevated pathological levels of reactive oxygen species (ROS), which trigger Baeyer-Villiger oxidation of the 1,2-dicarbonyl moiety, resulting in rapid hydrolysis of the generated anhydride and localized MMF release. Interestingly, 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, compounds 4, 5, and 6, with trideuteromethyl, ethyl, and iso-propyl esters, respectively, exhibit strong tissue-specific NRF2 activation, and 4 in particular demonstrated full reversal of mechanical allodynia in a mouse model of neuropathy.