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

Qing Jing; Huiying Li; Georges Chreifi; Linda J. Roman; Pavel Martásek; Thomas L. Poulos; Richard B. Silverman

doi:10.1016/j.bmcl.2013.08.034

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

Qing Jing, Huiying Li, Georges Chreifi, Linda J. Roman, Pavel Martásek, Thomas L. Poulos^*, Richard B. Silverman

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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 aminomethyl moiety 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.

Original language	English (US)
Pages (from-to)	5674-5679
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2013.08.034
State	Published - Oct 15 2013

Funding

The authors are grateful for financial support from the National Institutes of Health ( GM049725 to R.B.S. and GM057353 to T.L.P.). We thank Dr. Bettie Sue Siler Masters (NIH grant GM52419, with whose laboratory P.M. and L.J.R. are affiliated). B.S.S.M. also acknowledges the Welch Foundation for a Robert A. Welch Distinguished Professorship in Chemistry (AQ0012). P.M. is supported by grants 0021620849 from MSMT of the Czech Republic. We also thank the beamline staff at SSRL and ALS for their assistance during the remote X-ray diffraction data collections.

Keywords

Chiral molecules
Crystallography
Double-headed inhibitors
Inhibition
Neuronal nitric oxide synthase

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmaceutical Science
Organic Chemistry

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10.1016/j.bmcl.2013.08.034

Cite this

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title = "Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors",

abstract = "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 aminomethyl moiety 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.",

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author = "Qing Jing and Huiying Li and Georges Chreifi and Roman, {Linda J.} and Pavel Mart{\'a}sek and Poulos, {Thomas L.} and Silverman, {Richard B.}",

note = "Funding Information: The authors are grateful for financial support from the National Institutes of Health ( GM049725 to R.B.S. and GM057353 to T.L.P.). We thank Dr. Bettie Sue Siler Masters (NIH grant GM52419, with whose laboratory P.M. and L.J.R. are affiliated). B.S.S.M. also acknowledges the Welch Foundation for a Robert A. Welch Distinguished Professorship in Chemistry (AQ0012). P.M. is supported by grants 0021620849 from MSMT of the Czech Republic. We also thank the beamline staff at SSRL and ALS for their assistance during the remote X-ray diffraction data collections. ",

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AU - Jing, Qing

AU - Li, Huiying

AU - Chreifi, Georges

AU - Roman, Linda J.

AU - Martásek, Pavel

AU - Poulos, Thomas L.

AU - Silverman, Richard B.

N1 - Funding Information: The authors are grateful for financial support from the National Institutes of Health ( GM049725 to R.B.S. and GM057353 to T.L.P.). We thank Dr. Bettie Sue Siler Masters (NIH grant GM52419, with whose laboratory P.M. and L.J.R. are affiliated). B.S.S.M. also acknowledges the Welch Foundation for a Robert A. Welch Distinguished Professorship in Chemistry (AQ0012). P.M. is supported by grants 0021620849 from MSMT of the Czech Republic. We also thank the beamline staff at SSRL and ALS for their assistance during the remote X-ray diffraction data collections.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - 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 aminomethyl moiety 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.

AB - 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 aminomethyl moiety 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.

KW - Chiral molecules

KW - Crystallography

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KW - Inhibition

KW - Neuronal nitric oxide synthase

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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Structure of bovine endothelial nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amine

Structure of neuronal nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amine

Structure of bovine endothelial nitric oxide synthase heme domain in complex with (S)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-propan-3-amine

Cite this

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Datasets

Structure of bovine endothelial nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amine

Structure of neuronal nitric oxide synthase heme domain in complex with (S)-1,3-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-butan-4-amine

Structure of bovine endothelial nitric oxide synthase heme domain in complex with (S)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-propan-3-amine

Cite this