Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F14%3A10283792" target="_blank" >RIV/00216208:11110/14:10283792 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1021/ml400381s" target="_blank" >http://dx.doi.org/10.1021/ml400381s</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/ml400381s" target="_blank" >10.1021/ml400381s</a>

Result language
angličtina
Original language name
Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors
Original language 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 prop
Czech name
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Czech description
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Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
CE - Biochemistry
OECD FORD branch
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Publication year
2014
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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