184485-83-4Relevant articles and documents
Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors
Richardson, Benjamin G.,Jain, Atul D.,Potteti, Haranatha R.,Lazzara, Phillip R.,David, Brian P.,Tamatam, Chandra R.,Choma, Ewelina,Skowron, Kornelia,Dye, Katherine,Siddiqui, Zamia,Wang, Yue-Ting,Krunic, Aleksej,Reddy, Sekhar P.,Moore, Terry W.
, p. 8029 - 8047 (2018/09/12)
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.
