Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability.
JOURNAL OF MEDICINAL CHEMISTRY(2020)
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 logD(7.4) 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.
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Key words
inhibitors,metabolic,kelch-like,ech-associated,erythroid-derived
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