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PDBsum entry 5adc
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Oxidoreductase
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PDB id
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5adc
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References listed in PDB file
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Key reference
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Title
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Phenyl ether- And aniline-Containing 2-Aminoquinolines as potent and selective inhibitors of neuronal nitric oxide synthase.
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Authors
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M.A.Cinelli,
H.Li,
A.V.Pensa,
S.Kang,
L.J.Roman,
P.Martásek,
T.L.Poulos,
R.B.Silverman.
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Ref.
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J Med Chem, 2015,
58,
8694-8712.
[DOI no: ]
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PubMed id
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Abstract
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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.
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