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

被引:45
作者
Richardson, Benjamin G. [1 ]
Jain, Atul D. [1 ]
Potteti, Haranatha R. [2 ]
Lazzara, Phillip R. [1 ]
David, Brian P. [1 ]
Tamatam, Chandra R. [2 ]
Choma, Ewelina [1 ]
Skowron, Kornelia [1 ]
Dye, Katherine [3 ]
Siddiqui, Zamia [1 ]
Wang, Yue-Ting [3 ,4 ]
Krunic, Aleksej [1 ]
Reddy, Sekhar P. [2 ,5 ]
Moore, Terry W. [1 ,3 ,5 ]
机构
[1] Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, 833 South Wood St, Chicago, IL 60612 USA
[2] Univ Illinois, Dept Pediat, Coll Med, 833 South Wood St, Chicago, IL 60612 USA
[3] Univ Illinois, UICtr Drug Discovery, 833 South Wood St, Chicago, IL 60612 USA
[4] Univ Illinois, Mass Spectrometry Core, Res Resources Ctr, 833 South Wood St, Chicago, IL 60612 USA
[5] Univ Illinois, Canc Ctr, 833 South Wood St, Chicago, IL 60612 USA
关键词
ANTIOXIDANT RESPONSE ELEMENT; TRANSCRIPTION FACTOR NRF2; CATION-PI INTERACTIONS; RECOGNITION MODEL; COVALENT BINDING; OXIDATIVE STRESS; IN-VIVO; KEAP1; DISCOVERY; MECHANISM;
D O I
10.1021/acs.jmedchem.8b01133
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:8029 / 8047
页数:19
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