Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F13%3A10189198" target="_blank" >RIV/00216208:11110/13:10189198 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1016/j.bmcl.2013.08.034" target="_blank" >http://dx.doi.org/10.1016/j.bmcl.2013.08.034</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bmcl.2013.08.034" target="_blank" >10.1016/j.bmcl.2013.08.034</a>

Result language
angličtina
Original language name
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors
Original language description
To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32 nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethylmoiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization.
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
2013
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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