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Statements

Subject Item
n2:RIV%2F00216208%3A11110%2F14%3A10283796%21RIV15-MSM-11110___
rdf:type
n3:Vysledek skos:Concept
rdfs:seeAlso
http://dx.doi.org/10.1021/jm401838x
dcterms:description
Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic L-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability. Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic L-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability.
dcterms:title
Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition
skos:prefLabel
Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition
skos:notation
RIV/00216208:11110/14:10283796!RIV15-MSM-11110___
n4:aktivita
n10:P n10:Z
n4:aktivity
P(1M0520), Z(MSM0021620806)
n4:cisloPeriodika
4
n4:dodaniDat
n6:2015
n4:domaciTvurceVysledku
n11:4688678
n4:druhVysledku
n13:J
n4:duvernostUdaju
n14:S
n4:entitaPredkladatele
n19:predkladatel
n4:idSjednocenehoVysledku
44908
n4:idVysledku
RIV/00216208:11110/14:10283796
n4:jazykVysledku
n20:eng
n4:klicovaSlova
disease; dihydroquinolines; model; design; in-vitro; cerebral-palsy; escherichia-coli; biological evaluation; active-site; n-nos inhibitors
n4:klicoveSlovo
n5:dihydroquinolines n5:escherichia-coli n5:cerebral-palsy n5:n-nos%20inhibitors n5:in-vitro n5:disease n5:active-site n5:biological%20evaluation n5:model n5:design
n4:kodStatuVydavatele
US - Spojené státy americké
n4:kontrolniKodProRIV
[77885FA72685]
n4:nazevZdroje
Journal of Medicinal Chemistry
n4:obor
n21:CE
n4:pocetDomacichTvurcuVysledku
1
n4:pocetTvurcuVysledku
7
n4:projekt
n18:1M0520
n4:rokUplatneniVysledku
n6:2014
n4:svazekPeriodika
57
n4:tvurceVysledku
Martásek, Pavel Chreifi, Georges Silverman, Richard B. Roman, Linda J. Poulos, Thomas L. Li, Huiying Cinelli, Maris A.
n4:wos
000332187700028
n4:zamer
n12:MSM0021620806
s:issn
0022-2623
s:numberOfPages
18
n17:doi
10.1021/jm401838x
n9:organizacniJednotka
11110