Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors

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.