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Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.

Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martásek P, Poulos TL, Silverman RB
J Med Chem 58 8694-712 (2015)
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Cited: 12 times
EuropePMC logo PMID: 26469213

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, endothelial NOS (eNOS), and 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.

Articles - 5add mentioned but not cited (1)

  1. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martásek P, Poulos TL, Silverman RB. J Med Chem 58 8694-8712 (2015)


Reviews citing this publication (2)

  1. Nitric oxide synthase and structure-based inhibitor design. Poulos TL, Li H. Nitric Oxide 63 68-77 (2017)
  2. The latest advances in the discovery of nitric oxide hybrid drug compounds. Serafim RAM, Pernichelle FG, Ferreira EI. Expert Opin Drug Discov 12 941-953 (2017)

Articles citing this publication (9)

  1. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB. J. Med. Chem. 60 3958-3978 (2017)
  2. Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 59 4913-4925 (2016)
  3. Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. Pensa AV, Cinelli MA, Li H, Chreifi G, Mukherjee P, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 60 7146-7165 (2017)
  4. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. Do HT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 62 2690-2707 (2019)
  5. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 63 4528-4554 (2020)
  6. Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. Do HT, Wang HY, Li H, Chreifi G, Poulos TL, Silverman RB. J. Med. Chem. 60 9360-9375 (2017)
  7. Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Tong S, Cinelli MA, El-Sayed NS, Huang H, Patel A, Silverman RB, Yang S. Sci Rep 12 1701 (2022)
  8. Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Dong J, Li D, Kang L, Luo C, Wang J. Biophys Rep 9 159-175 (2023)
  9. TsOH·H2O-mediated N-amidation of quinoline N-oxides: facile and regioselective synthesis of N-(quinolin-2-yl)amides. Chen X, Peng M, Huang H, Zheng Y, Tao X, He C, Xiao Y. Org. Biomol. Chem. 16 6202-6205 (2018)


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