Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors

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

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

Original languageEnglish (US)
Pages (from-to)7146-7165
Number of pages20
JournalJournal of Medicinal Chemistry
Volume60
Issue number16
DOIs
StatePublished - Aug 24 2017

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Pensa, A. V., Cinelli, M. A., Li, H., Chreifi, G., Mukherjee, P., Roman, L. J., Martásek, P., Poulos, T. L., & Silverman, R. B. (2017). Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. Journal of Medicinal Chemistry, 60(16), 7146-7165. https://doi.org/10.1021/acs.jmedchem.7b00835