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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)

Cited: 6 times
EuropePMC logo PMID: 28776992

Abstract

Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

Articles - 5vui mentioned but not cited (1)

  1. 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)


Articles citing this publication (5)

  1. 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)
  2. 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)
  3. 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)
  4. 7-Nitroindazole reduces L-DOPA-induced dyskinesias in non-human Parkinsonian primate. Herrero MT, Yuste JE, Cuenca-Bermejo L, Almela P, Arenas-Betancur L, De Pablos V, Gonzalez-Cuello A, Del Bel E, Navarro-Zaragoza J, Fernández-Villalba E. Open Biol 13 220370 (2023)
  5. 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)


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