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Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

Title
Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase
Authors
Cinelli, Maris A.Li, HuiyingPensa, Anthony V.Kang, SoosungRoman, Linda J.Martasek, PavelPoulos, Thomas L.Silverman, Richard B.
Ewha Authors
강수성
Issue Date
2015
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link

1520-4804JCR Link
Citation
JOURNAL OF MEDICINAL CHEMISTRY vol. 58, no. 21, pp. 8694 - 8712
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS
Document Type
Article
Abstract
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, 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.
DOI
10.1021/acs.jmedchem.5b01330
Appears in Collections:
약학대학 > 약학과 > Journal papers
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