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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.
Affiliation
  • Richardson BG; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Jain AD; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Lazzara PR; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • David BP; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Choma E; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Skowron K; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Siddiqui Z; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Krunic A; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
  • Moore TW; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wo
J Med Chem ; 61(17): 8029-8047, 2018 09 13.
Article in En | MEDLINE | ID: mdl-30122040
ABSTRACT
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Expression Regulation / NF-E2-Related Factor 2 / Small Molecule Libraries / Protein Interaction Domains and Motifs / Kelch-Like ECH-Associated Protein 1 / Isoquinolines / Naphthalenes Type of study: Risk_factors_studies Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2018 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Expression Regulation / NF-E2-Related Factor 2 / Small Molecule Libraries / Protein Interaction Domains and Motifs / Kelch-Like ECH-Associated Protein 1 / Isoquinolines / Naphthalenes Type of study: Risk_factors_studies Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2018 Document type: Article