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Statements

Subject Item
n2:RIV%2F00064165%3A_____%2F10%3A7216%21RIV11-MZ0-00064165
rdf:type
n14:Vysledek skos:Concept
dcterms:description
In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K-i of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K-i of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site.
dcterms:title
Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase
skos:prefLabel
Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase
skos:notation
RIV/00064165:_____/10:7216!RIV11-MZ0-00064165
n3:aktivita
n4:P n4:Z n4:I
n3:aktivity
I, P(1M0520), Z(MSM0021620806)
n3:cisloPeriodika
40
n3:dodaniDat
n13:2011
n3:domaciTvurceVysledku
n11:4688678
n3:druhVysledku
n17:J
n3:duvernostUdaju
n9:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
280461
n3:idVysledku
RIV/00064165:_____/10:7216
n3:jazykVysledku
n15:eng
n3:klicovaSlova
escherichia-coli; messenger-rna; disease; model; refinement; design
n3:klicoveSlovo
n5:model n5:disease n5:refinement n5:messenger-rna n5:design n5:escherichia-coli
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[1AC186761418]
n3:nazevZdroje
Journal of the american chemical society
n3:obor
n12:CE
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
8
n3:projekt
n10:1M0520
n3:rokUplatneniVysledku
n13:2010
n3:svazekPeriodika
132
n3:tvurceVysledku
Delker, Silvia L. Silverman, Richard B. Martásek, Pavel Fang, Janguo Roman, Linda J. Xue, Fengtian Poulos, Thomas L. Li, Huiying
n3:wos
000282660100062
n3:zamer
n16:MSM0021620806
s:issn
0002-7863
s:numberOfPages
10