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Statements

Subject Item
n2:RIV%2F00216208%3A11110%2F14%3A10283792%21RIV15-MSM-11110___
rdf:type
skos:Concept n16:Vysledek
rdfs:seeAlso
http://dx.doi.org/10.1021/ml400381s
dcterms:description
The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily synthesized compounds containing either one (20a,b) or two (9a-d; 15a,b) 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor 9c is the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either 9a or 9c show a double-headed binding mode, where each 2-aminopyridine headgroup interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of 9c contributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of 9a to the heme propionate allows the inhibitor to adopt two different binding orientations. Both 9a and 9c bind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity. The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily synthesized compounds containing either one (20a,b) or two (9a-d; 15a,b) 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor 9c is the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either 9a or 9c show a double-headed binding mode, where each 2-aminopyridine headgroup interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of 9c contributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of 9a to the heme propionate allows the inhibitor to adopt two different binding orientations. Both 9a and 9c bind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity.
dcterms:title
Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors
skos:prefLabel
Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors
skos:notation
RIV/00216208:11110/14:10283792!RIV15-MSM-11110___
n5:aktivita
n13:Z
n5:aktivity
Z(MSM0021620849)
n5:cisloPeriodika
1
n5:dodaniDat
n9:2015
n5:domaciTvurceVysledku
n15:4688678
n5:druhVysledku
n20:J
n5:duvernostUdaju
n17:S
n5:entitaPredkladatele
n19:predkladatel
n5:idSjednocenehoVysledku
1409
n5:idVysledku
RIV/00216208:11110/14:10283792
n5:jazykVysledku
n8:eng
n5:klicovaSlova
neurodegenerative diseases; enzyme inhibition; nitric oxide synthase; Nitric oxide
n5:klicoveSlovo
n7:Nitric%20oxide n7:enzyme%20inhibition n7:neurodegenerative%20diseases n7:nitric%20oxide%20synthase
n5:kodStatuVydavatele
US - Spojené státy americké
n5:kontrolniKodProRIV
[6374CF13A9E9]
n5:nazevZdroje
ACS Medicinal Chemistry Letters
n5:obor
n14:CE
n5:pocetDomacichTvurcuVysledku
1
n5:pocetTvurcuVysledku
6
n5:rokUplatneniVysledku
n9:2014
n5:svazekPeriodika
5
n5:tvurceVysledku
Li, Huiying Roman, Linda J. Martásek, Pavel Silverman, Richard B. Jing, Qing Poulos, Thomas L.
n5:wos
000329677900013
n5:zamer
n12:MSM0021620849
s:issn
1948-5875
s:numberOfPages
5
n11:doi
10.1021/ml400381s
n10:organizacniJednotka
11110