Abstract
Pharmacological activation of NRF2 (nuclear factor erythroid 2-related factor 2) arises from blocking the interaction of NRF2 with its negative regulator, KEAP1 (Kelch-like ECH-associated protein 1). We previously reported an isoquinoline-based NRF2 activator, but this compound showed negative logD7.4 and a -2 charge at physiological pH, which may have limited its membrane permeability. In this work, we report potent, metabolically stable analogs that result from replacing a carboxymethyl group at the 4-position with a fluoroalkyl group.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Drug Discovery*
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Drug Stability
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Humans
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Isoquinolines / chemistry*
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Isoquinolines / pharmacology*
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Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors*
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NF-E2-Related Factor 2 / antagonists & inhibitors*
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Protein Binding
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology*
Substances
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Isoquinolines
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Small Molecule Libraries