MMF prodrug-1c

MMF prodrug-1c is a cell permeable activator of NRF2. A site-specific monomethyl fumarate (MMF) prodrug (1c) achieves targeted delivery of MMF through a peroxide-dependent Baeyer-Villiger oxidation mechanism, selectively activating NRF2 at sites of pathological oxidative stress. Upon oral administration, MMF prodrug-1c rapidly converts to a stable glutathione S-conjugate that circulates until encountering elevated peroxide concentrations (>1 μM H2O2 or >20 μM peroxynitrite) at disease sites, where it releases therapeutic MMF while avoiding indiscriminate NRF2 activation in healthy tissues. At an optimal dose of 350 μmol/kg/day, MMF prodrug-1c demonstrates superior efficacy to conventional MMF delivery in multiple chronic pain models, reversing peripheral neuropathy, osteoarthritis, and chemotherapy-induced neuropathic pain without inducing systemic side effects like glutathione depletion or cutaneous flushing.