 |
PDBsum entry 5uo2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase/oxidoreductase inhibitor
|
PDB id
|
|
|
|
5uo2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Nitrile in the hole: discovery of a small auxiliary pocket in neuronal nitric oxide synthase leading to the development of potent and selective 2-Aminoquinoline inhibitors.
|
|
|
Authors
|
|
M.A.Cinelli,
H.Li,
G.Chreifi,
T.L.Poulos,
R.B.Silverman.
|
|
|
Ref.
|
|
J Med Chem, 2017,
60,
3958-3978.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to
treat neurodegenerative disorders, but the development of nNOS inhibitors is
often hindered by poor pharmacokinetics. We previously developed a class of
membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold
to decrease off-target binding. However, the resulting compounds had decreased
permeability, low human nNOS activity, and low selectivity versus human eNOS. In
this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives
were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds
are especially potent and selective rat and human nNOS inhibitors. Activity and
selectivity are mediated by the binding of the cyano group to a new auxiliary
pocket in nNOS. Potency was enhanced by methylation of the quinoline and by
introduction of simple chiral moieties, resulting in a combination of
hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e
selectivity. Importantly, the Caco-2 assay also revealed improved membrane
permeability over previous compounds.
|
|
|
|
|
|
|
