Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 17, Pages 8029-8047Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01133
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Funding
- National Institute of Arthritis, Musculoskeletal and Skin Diseases [1R01 AR069S41-01A1]
- National Heart, Lung, and Blood Institute [1R01 HL136946-01]
- Chancellor's Discovery Fund at UIC
- Michael Reese Research and Education Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL136946] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR069541] Funding Source: NIH RePORTER
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Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhibition of the KEAP1/NRF2 interaction with small molecules leads to NRF2 activation. Previously, we and others described naphthalene-based NRF2 activators, but the 1,4-diaminonaphthalene scaffold may not represent a drug-like scaffold. Paying particular attention to aqueous solubility, metabolic stability, potency, and mutagenicity, we modified a previously known, naphthalene-based nonelectrophilic NRF2 activator to give a series of non-naphthalene and heterocyclic scaffolds. We found that, compared to previously reported naphthalene-based compounds, a 1,4-isoquinoline scaffold provides a better mutagenic profile without sacrificing potency, stability, or solubility.
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