Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition

Maris A. Cinelli, Huiying Li, Georges Chreifi, Pavel Martásek, Linda J. Roman, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability.

Original languageEnglish (US)
Pages (from-to)1513-1530
Number of pages18
JournalJournal of Medicinal Chemistry
Volume57
Issue number4
DOIs
Publication statusPublished - Feb 27 2014

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Cinelli, M. A., Li, H., Chreifi, G., Martásek, P., Roman, L. J., Poulos, T. L., & Silverman, R. B. (2014). Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition. Journal of Medicinal Chemistry, 57(4), 1513-1530. https://doi.org/10.1021/jm401838x