Abstract
A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered 17, which showed excellent potency toward both rat (Ki 15 nM) and human nNOS (Ki 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. 17 also showed excellent permeability (Pe = 13.7 × 10-6 cm s-1), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.
Original language | English (US) |
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Pages (from-to) | 9934-9953 |
Number of pages | 20 |
Journal | Journal of Medicinal Chemistry |
Volume | 66 |
Issue number | 14 |
DOIs | |
State | Published - Jul 27 2023 |
Funding
We thank Radoslaw T. Chrzanowski for assistance in the MOE docking studies. This work made use of the IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois and International Institute for Nanotechnology (IIN). We also thank the beamline staff at SSRL and ALS for their assistance during the remote X-ray diffraction data collections. We are grateful for the generous support from the National Institutes of Health (R35GM131788 to R.B.S.; GM057353 and GM131920 to T.L.P.). We thank Radoslaw T. Chrzanowski for assistance in the MOE docking studies. This work made use of the IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois and International Institute for Nanotechnology (IIN). We also thank the beamline staff at SSRL and ALS for their assistance during the remote X-ray diffraction data collections. We are grateful for the generous support from the National Institutes of Health (R35GM131788 to R.B.S.; GM057353 and GM131920 to T.L.P.).
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
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Dive into the research topics of 'Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors'. Together they form a unique fingerprint.Datasets
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Structure of rat neuronal nitric oxide synthase R349A mutant heme domain in complex with 4-(difluoromethyl)-6-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)pyridin-2-amine dihydrochloride
Vasu, D. (Contributor), Do, H. T. (Contributor), Li, H. (Contributor), Hardy, C. D. (Contributor), Awasthi, A. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Oct 11 2023
DOI: 10.2210/pdb8FGE/pdb, https://www.wwpdb.org/pdb?id=pdb_00008fge
Dataset
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Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)-4-methoxypyridin-2-amine
Vasu, D. (Contributor), Do, H. T. (Contributor), Li, H. (Contributor), Hardy, C. D. (Contributor), Awasthi, A. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Oct 11 2023
DOI: 10.2210/pdb8FGH/pdb, https://www.wwpdb.org/pdb?id=pdb_00008fgh
Dataset
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Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 4-(difluoromethyl)-6-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)pyridin-2-amine
Vasu, D. (Contributor), Do, H. T. (Contributor), Li, H. (Contributor), Hardy, C. D. (Contributor), Awasthi, A. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Oct 11 2023
DOI: 10.2210/pdb8FGM/pdb, https://www.wwpdb.org/pdb?id=pdb_00008fgm
Dataset