Abstract
In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pKa NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.
Original language | English (US) |
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Pages (from-to) | 14229-14238 |
Number of pages | 10 |
Journal | Journal of the American Chemical Society |
Volume | 132 |
Issue number | 40 |
DOIs | |
State | Published - Oct 13 2010 |
ASJC Scopus subject areas
- General Chemistry
- Biochemistry
- Catalysis
- Colloid and Surface Chemistry
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(((3R,4R)-4-(2-(2,2-Difluoro-2-phenylethylamino)ethoxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine
Xue, F. (Contributor), Li, H. (Contributor), Delker, S. L. (Contributor), Fang, J. (Contributor), Martásek, P. (Contributor), Roman, L. J. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Jan 19 2011
DOI: 10.2210/pdb3NLZ/pdb, https://www.wwpdb.org/pdb?id=pdb_00003nlz
Dataset
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(((3S,4S)-4-(2-(2,2-Difluoro-2-(piperidin-2-yl)ethylamino)ethoxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine
Xue, F. (Contributor), Li, H. (Contributor), Delker, S. L. (Contributor), Fang, J. (Contributor), Martásek, P. (Contributor), Roman, L. J. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Jan 19 2011
DOI: 10.2210/pdb3NLW/pdb, https://www.wwpdb.org/pdb?id=pdb_00003nlw
Dataset
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Structure of endothelial nitric oxide synthase heme domain complexed with N1-{(3'S,4'S)-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}- N2-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride
Xue, F. (Contributor), Li, H. (Contributor), Delker, S. L. (Contributor), Fang, J. (Contributor), Martásek, P. (Contributor), Roman, L. J. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Jan 19 2011
DOI: 10.2210/pdb3NLT/pdb, https://www.wwpdb.org/pdb?id=pdb_00003nlt
Dataset