1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

doi:10.1016/j.bmcl.2011.07.022

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 18, 15 September 2011, Pages 5301-5304

https://doi.org/10.1016/j.bmcl.2011.07.022 Get rights and content

Abstract

A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (−)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC₅₀ = 0.02 μM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS = 96-fold) and iNOS (iNOS/nNOS = 850-fold) isoforms.

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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.

References and notes (27)

S. Maddaford et al.
Annu. Rep. Med. Chem.
(2009)
J. Patman et al.
Bioorg. Med. Chem. Lett.
(2007)
M.J. O’Neill et al.
Brain Res.
(2000)
S. Jaroch et al.
Bioorg. Med. Chem. Lett.
(2003)
R.J. DeVita et al.
Bioorg. Med. Chem. Lett.
(1999)
J.W. Coe et al.
Tetrahedron Lett.
(1996)
L.J. Ignarro et al.
Proc. Natl. Acad. Sci. U.S.A.
(1987)
R.F. Furchgott
P. Vallance et al.
Nat. Rev. Drug Disc.
(2002)
A.J. Cayatte et al.
Arterioscler. Thromb.
(1994)

J. Haitao et al.

J. Med. Chem.

(2009)

E.P. Erdal et al.

Curr. Top. Med. Chem.

(2005)

R.B. Silverman

Acc. Chem. Res.

(2009)

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1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Abstract

Graphical abstract

Section snippets

Acknowledgments

Annu. Rep. Med. Chem.

Bioorg. Med. Chem. Lett.

Brain Res.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Tetrahedron Lett.

Proc. Natl. Acad. Sci. U.S.A.

Nat. Rev. Drug Disc.

Arterioscler. Thromb.

J. Med. Chem.

Curr. Top. Med. Chem.

Acc. Chem. Res.