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PDBsum entry 6pp2
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Oxidoreductase/inhibitor
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PDB id
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6pp2
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References listed in PDB file
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Key reference
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Title
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First contact: 7-Phenyl-2-Aminoquinolines, Potent and selective neuronal nitric oxide synthase inhibitors that target an isoform-Specific aspartate.
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Authors
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M.A.Cinelli,
C.T.Reidl,
H.Li,
G.Chreifi,
T.L.Poulos,
R.B.Silverman.
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Ref.
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J Med Chem, 2020,
63,
4528-4554.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in
neurodegenerative disorders, is an attractive strategy for treating or
preventing these diseases. We previously developed several classes of
2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks
including off-target promiscuity, low activity against human nNOS, and only
modest selectivity for nNOS over related enzymes. In this study, we synthesized
new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against
rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS.
Compounds with a meta-relationship between the aminoquinoline and a
positively charged tail moiety were potent and had up to nearly 900-fold
selectivity for human nNOS over human eNOS. X-ray crystallography indicates that
the amino groups of some compounds occupy a water-filled pocket surrounding an
nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed
by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first
aminoquinolines to interact with this residue.
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