Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.

BIOCEV Prague Czech Republic

Department of Biochemistry University of Texas Health Science Center San Antonio Texas 78384 7760 United States

Department of Chemistry Department of Molecular Biosciences Chemistry of Life Processes Institute Center for Molecular Innovation and Drug Discovery Northwestern University 2145 Sheridan Road Evanston Illinois 60208 3113 United States

Department of Pediatrics 1st Faculty of Medicine Charles University Prague Czech Republic

Departments of Molecular Biology and Biochemistry Pharmaceutical Sciences and Chemistry University of California Irvine California 92697 3900 United States

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J Med Chem. 2016 Feb 11;59(3):1246. doi: 10.1021/acs.jmedchem.6b00036. PubMed

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

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PDB
5AD4, 5AD5, 5AD6, 5AD8, 5AD9, 5ADA, 5ADB, 5ADC, 5ADD, 5ADE, 5ADF, 5ADG, 5ADI, 5ADJ, 5ADK, 5ADL, 5ADN, 5FJ2, 5FJ3