Optimization of 3-Aminotetrahydrothiophene 1,1-Dioxides with Improved Potency and Efficacy as Non-Electrophilic Antioxidant Response Element (ARE) Activators
6 Pages Posted: 8 Mar 2023
Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17, a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17, 18, and 22 will likely be of pharmacological utility.
Keywords: ARE activator, NRF2, Non-electrophilic, PGK1 inhibitor, Drug-likeness
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