Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability

J Med Chem. 2020 Jun 25;63(12):6547-6560. doi: 10.1021/acs.jmedchem.9b01074. Epub 2019 Nov 14.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Drug Discovery*
  • Drug Stability
  • Humans
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • Protein Binding
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*

Substances

  • Isoquinolines
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Small Molecule Libraries