Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F16%3A10327247" target="_blank" >RIV/00216208:11110/16:10327247 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1021/acs.jmedchem.6b00273" target="_blank" >http://dx.doi.org/10.1021/acs.jmedchem.6b00273</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.6b00273" target="_blank" >10.1021/acs.jmedchem.6b00273</a>
Alternative languages
Result language
angličtina
Original language name
Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker
Original language description
Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (K-i = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a K-i value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.
Czech name
—
Czech description
—
Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
CE - Biochemistry
OECD FORD branch
—
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Medicinal Chemistry
ISSN
0022-2623
e-ISSN
—
Volume of the periodical
59
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
4913-4925
UT code for WoS article
000376840600039
EID of the result in the Scopus database
2-s2.0-84971612221