About: Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition

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An Entity of Type : http://linked.opendata.cz/ontology/domain/vavai/Vysledek, within Data Space : linked.opendata.cz associated with source document(s)

Attributes	Values
rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
rdfs:seeAlso	http://dx.doi.org/10.1021/jm401838x
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. (en)
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 (en)
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 (en)
skos:notation	RIV/00216208:11110/14:10283796!RIV15-MSM-11110___
http://linked.open...avai/riv/aktivita	P Z
http://linked.open...avai/riv/aktivity	P(1M0520), Z(MSM0021620806)
http://linked.open...iv/cisloPeriodika	4
http://linked.open...vai/riv/dodaniDat	2015
http://linked.open...aciTvurceVysledku	Martásek, Pavel
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Univerzita Karlova v Praze / 1. lékařská fakulta
http://linked.open...dnocenehoVysledku	44908
http://linked.open...ai/riv/idVysledku	RIV/00216208:11110/14:10283796
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	disease; dihydroquinolines; model; design; in-vitro; cerebral-palsy; escherichia-coli; biological evaluation; active-site; n-nos inhibitors (en)
http://linked.open.../riv/klicoveSlovo	escherichia-coli active-site cerebral-palsy dihydroquinolines n-nos inhibitors design disease model biological evaluation in-vitro
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[77885FA72685]
http://linked.open...i/riv/nazevZdroje	Journal of Medicinal Chemistry
http://linked.open...in/vavai/riv/obor	CE
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	7 (xsd:int)
http://linked.open...vavai/riv/projekt	Center for Applied Genomics
http://linked.open...UplatneniVysledku	2014
http://linked.open...v/svazekPeriodika	57
http://linked.open...iv/tvurceVysledku	Martásek, Pavel Chreifi, Georges Li, Huiying Poulos, Thomas L. Roman, Linda J. Silverman, Richard B. Cinelli, Maris A.
http://linked.open...ain/vavai/riv/wos	000332187700028
http://linked.open...n/vavai/riv/zamer	Molekulární biologie a patologie buňky za normy a u vybraných klinicky závažných patologických procesů
issn	0022-2623
number of pages	18 (xsd:int)
http://bibframe.org/vocab/doi	10.1021/jm401838x
http://localhost/t...ganizacniJednotka	11110

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