Abstract
In certain neurodegenerative diseases damaging levels of nitric oxide (NO) are produced by neuronal nitric oxide synthase (nNOS). It, therefore, is important to develop inhibitors selective for nNOS that do not interfere with other NOS isoforms, especially endothelial NOS (eNOS), which is critical for proper functioning of the cardiovascular system. While we have been successful in developing potent and isoform-selective inhibitors, such as lead compounds 1 and 2, the ease of synthesis and bioavailability have been problematic. Here we describe a new series of compounds including crystal structures of NOS-inhibitor complexes that integrate the advantages of easy synthesis and good biological properties compared to the lead compounds. These results provide the basis for additional structure-activity relationship (SAR) studies to guide further improvement of isozyme selective inhibitors.
Original language | English (US) |
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Pages (from-to) | 5323-5331 |
Number of pages | 9 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 21 |
Issue number | 17 |
DOIs | |
State | Published - Sep 1 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 0021620806 and 1M0520 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
- Aminopyridines
- Inhibition
- Neuronal nitric oxide synthase
- Nitric oxide
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Molecular Biology
- Biochemistry
- Clinical Biochemistry
- Pharmaceutical Science
- Organic Chemistry
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Dive into the research topics of 'In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures'. Together they form a unique fingerprint.Datasets
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-((3-(((3-fluorophenethyl)amino)methyl)phenoxy)methyl)-4-methylpyridin-2-amine
Jing, Q. (Contributor), Li, H. (Contributor), Fang, J. (Contributor), Roman, L. J. (Contributor), Martásek, P. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Aug 7 2013
DOI: 10.2210/pdb4JSI/pdb, https://www.wwpdb.org/pdb?id=pdb_00004jsi
Dataset
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(((5-(((3-fluorophenethyl)amino)methyl)pyridin-3-yl)oxy)methyl)-4-methylpyridin-2-amine
Jing, Q. (Contributor), Li, H. (Contributor), Fang, J. (Contributor), Roman, L. J. (Contributor), Martásek, P. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Aug 7 2013
DOI: 10.2210/pdb4JSJ/pdb, https://www.wwpdb.org/pdb?id=pdb_00004jsj
Dataset
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-((3-(3-aminopropoxy)phenoxy)methyl)-4-methylpyridin-2-amine
Jing, Q. (Contributor), Li, H. (Contributor), Fang, J. (Contributor), Roman, L. J. (Contributor), Martásek, P. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Aug 7 2013
DOI: 10.2210/pdb4JSG/pdb, https://www.wwpdb.org/pdb?id=pdb_00004jsg
Dataset