1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors
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Acknowledgments
We are grateful to NoAb BioDiscoveries Inc. (Mississauga, ON, Canada) and Asinex Ltd (Moscow, Russia) for performing the human NOS inhibition assays. We thank the Natural Sciences and Engineering Research Council (NSERC) of Canada for providing an Industrial Research Fellowship to GM.
References and notes (23)
- et al.
Annu. Rep. Med. Chem.
(2009) - et al.
Cell
(1998) - et al.
J. Biol. Chem.
(1999) - et al.
Bioorg. Med. Chem. Lett.
(2007) - et al.
Bioorg. Med. Chem. Lett.
(1999) - et al.
Sci. Signal.
(2009) - et al.
Nat. Rev. Drug Disc.
(2002) - et al.
Arterioscler. Thromb.
(1994) - et al.
J. Med. Chem.
(2009) - et al.
Nat. Struct. Biol.
(1999)
Science
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