Nuclear factor erythroid 2–related factor 2, or NRF2, is a key protein responsible for the regulation of numerous signaling pathways in the body, particularly those related to oxidative stress and cytokine release. As a result, NRF2 has been considered as a potential drug target in the treatment of inflammatory diseases and diseases that lead to malignant inflammatory responses such as multiple sclerosis, liver disease, diabetes, and chronic obstructive pulmonary disease. Studies show that electrophilic activators of NRF2 are promiscuous and may lead to potentially dangerous off-target effects when used in the body, prompting the development of non-electrophilic activators such as that being studied currently, PRL-295. Although testing in the chronic wound healing of diabetic mice has shown PRL-295 to be an effective NRF2 activator <i>in-vivo</i>, optimization of the compound’s pharmacokinetic properties such as cellular permeability is essential. In an effort to increase cell permeability and lipophilicity of the compound, we have synthesized a series of PRL-295 prodrugs and bioisosteres, which will replace the carboxylic moiety of the original compound. With further testing, we hope to demonstrate improved pharmacological activity.

Synthesis of non-electrophilic, NRF2-activating prodrugs

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ACS Fall 2022

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