Chronic, non-healing wounds of the skin are serious medical complications that affect over 6.5 million Americans, especially diabetic patients and older adults. Strikingly, there are almost no pharmaceutical therapies to accelerate healing of chronic wounds. A major contributor to chronic wounds is a prolonged inflammatory state, and reducing inflammation may be a way to accelerate healing of chronic wounds. Unfortunately, many commonly used anti-inflammatory drugs hinder chronic wound healing; thus, new ways of reducing inflammation are needed. An essential factor in wound healing and an important regulator of inflammation, NRF2 is a transcription factor that induces many cytoprotective and antioxidant genes. As seen in other inflammatory disorders, activating NRF2 could be a useful therapeutic strategy to treat chronic skin wounds. Non-covalent NRF2 activators can be developed by inhibiting the interaction of NRF2 with its negative regulator, KEAP1. We have developed a structure-activity relationship around a known, naphthalene-based non-covalent NRF2 activator, to create a NRF2 activator based on an isoquinoline scaffold. This work highlights some of the SAR work of the peripheral aryl rings, in the hopes of increasing metabolic stability, as well as positive charge to balance the overall charge of our lead compounds. The compounds’ affinities are tested in a fluorescence anisotropy assay. Western blot data shows compounds increase protein levels associated with NRF2. Using a mouse model, we show that one of these isoquinolines can decrease the time to wound healing in a mouse model.<br/>

Structure-activity relationship and evaluation of non-electrophilic NRF2 activators in a diabetic mouse model

2019 Fall National Meeting

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