Current therapeutics for neuropathic pain are poorly efficacious. One likely reason is that current therapies target only a single biochemical mechanism or pathway while chronic pain is a multi-mechanism problem. Fumarates, such as monomethyl fumarate (MMF), are uniquely positioned to treat the multi-mechanism problem of pain due to their combined antioxidant and anti-inflammatory profile. However, the risk-benefit ratio of fumarates is unacceptable for treatment of chronic pain, given their poor gastrointestinal tolerability and indiscriminate immune interference. This research project proposes to build on the documented analgesic efficacy of fumarates by designing new MMF prodrugs that have improved tolerability through design of non-reactive prodrugs. To reduce systemic immune interference, prodrugs will further be designed to preferentially release MMF, the active metabolite, only where ROS/RNS are overproduced in the pain neuraxis. The overall objective is to develop a 1,2-dicarbonyl prodrug that preferentially releases MMF at sites of pathology to alleviate neuropathic pain, while reducing adverse effects caused by systemic distribution of fumarates. Preliminary data indicate that the antioxidant master regulator nuclear factor erythroid 2-related factor 2 (NRF2) is a major therapeutic target. Using validated NRF2 activators and standard of care therapeutics as comparators, the UG3 specific aims are: 1) Complete initial characterization of the lead 1,2-dicarbonyl MMF prodrug; 2) Optimize lead compound, and design and evaluate backup 1,2-dicarbonyl MMF prodrugs; and 3) Characterize safety, validate analgesic efficacy of lead and backup 1,2-dicarbonyl MMF prodrugs. The exploratory milestones will identify a lead and backup molecules. These compounds will be advanced through IND-enabling studies under the following UH3 phase specific aims: 4) Extensive PK/PD characterization of candidates; 5) demonstrate in vivo efficacy in established rodent models of neuropathic pain; 6) Dose range finding to establish maximal tolerated dose (MTD) and cardiovascular, respiratory and gastrointestinal safety and toxicity studies; and 7) establish a Lead Development Team to finalize an IND application. BPN resources will be engaged for CMC manufacture and scale up, and development of a phase 1 clinical trial plan. Successful completion of this project will have major impact by first-in-class target activated delivery of a non-opioid therapeutic agent (MMF) to localized regions of pain pathology. Site-specific release of MMF will reduce its adverse effects, eliminating the final hurdles to MMF- based treatment of neuropathic pain.