First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate

Maris A. Cinelli, Cory T. Reidl, Huiying Li, Georges Chreifi, Thomas L. Poulos, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.

Original languageEnglish (US)
Pages (from-to)4528-4554
Number of pages27
JournalJournal of Medicinal Chemistry
Volume63
Issue number9
DOIs
StatePublished - May 14 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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