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Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase
- Title
- Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase
- Authors
- Cinelli, Maris A.; Li, Huiying; Pensa, Anthony V.; Kang, Soosung; Roman, Linda J.; Martasek, Pavel; Poulos, Thomas L.; Silverman, Richard B.
- Ewha Authors
- 강수성
- SCOPUS Author ID
- 강수성
- Issue Date
- 2015
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0022-2623
1520-4804
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY vol. 58, no. 21, pp. 8694 - 8712
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
- DOI
- 10.1021/acs.jmedchem.5b01330
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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