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J Med Chem. 2017 Aug 24;60(16):7146-7165. doi: 10.1021/acs.jmedchem.7b00835. Epub 2017 Aug 4.

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

Author information

1
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208-3113, United States.
2
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California , Irvine, California 92697-3900, United States.
3
Department of Biochemistry, University of Texas Health Science Center , San Antonio, Texas 78384-7760, United States.
4
Department of Pediatrics and Center for Applied Genomics, First School of Medicine, Charles University and BIOCEV 121 08 Prague, Czech Republic.

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.

PMID:
28776992
PMCID:
PMC5570656
DOI:
10.1021/acs.jmedchem.7b00835
[Indexed for MEDLINE]
Free PMC Article

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