Optimization of 3-aminotetrahydrothiophene 1,1-dioxides with improved potency and efficacy as non-electrophilic antioxidant response element (ARE) activators

Bioorg Med Chem Lett. 2023 Jun 1:89:129306. doi: 10.1016/j.bmcl.2023.129306. Epub 2023 Apr 26.

Abstract

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; Drug-likeness; NRF2; Non-electrophilic; PGK1 inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidant Response Elements*
  • Antioxidants* / pharmacology
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress

Substances

  • Antioxidants
  • NF-E2-Related Factor 2