Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors

Anthony V. Pensa, Maris A. Cinelli, Huiying Li, Georges Chreifi, Paramita Mukherjee, Linda J. Roman, Pavel Martásek, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7146-7165
Number of pages20
JournalJournal of Medicinal Chemistry
Volume60
Issue number16
DOIs
StatePublished - Aug 24 2017

Fingerprint

Aminoquinolines
Nitric Oxide Synthase Type I
Methylation
Biological Availability
Arginine
Permeability
Protein Isoforms
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. / Pensa, Anthony V.; Cinelli, Maris A.; Li, Huiying; Chreifi, Georges; Mukherjee, Paramita; Roman, Linda J.; Martásek, Pavel; Poulos, Thomas L.; Silverman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 60, No. 16, 24.08.2017, p. 7146-7165.

Research output: Contribution to journalArticle

Pensa, AV, Cinelli, MA, Li, H, Chreifi, G, Mukherjee, P, Roman, LJ, Martásek, P, Poulos, TL & Silverman, RB 2017, 'Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors', Journal of Medicinal Chemistry, vol. 60, no. 16, pp. 7146-7165. https://doi.org/10.1021/acs.jmedchem.7b00835
Pensa, Anthony V. ; Cinelli, Maris A. ; Li, Huiying ; Chreifi, Georges ; Mukherjee, Paramita ; Roman, Linda J. ; Martásek, Pavel ; Poulos, Thomas L. ; Silverman, Richard B. / Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 16. pp. 7146-7165.
@article{70aaad78d4524f008e1b680a0f85c7bb,
title = "Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors",
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.",
author = "Pensa, {Anthony V.} and Cinelli, {Maris A.} and Huiying Li and Georges Chreifi and Paramita Mukherjee and Roman, {Linda J.} and Pavel Mart{\'a}sek and Poulos, {Thomas L.} and Silverman, {Richard B.}",
year = "2017",
month = "8",
day = "24",
doi = "10.1021/acs.jmedchem.7b00835",
language = "English (US)",
volume = "60",
pages = "7146--7165",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "16",

}

TY - JOUR

T1 - Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors

AU - Pensa, Anthony V.

AU - Cinelli, Maris A.

AU - Li, Huiying

AU - Chreifi, Georges

AU - Mukherjee, Paramita

AU - Roman, Linda J.

AU - Martásek, Pavel

AU - Poulos, Thomas L.

AU - Silverman, Richard B.

PY - 2017/8/24

Y1 - 2017/8/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85028611428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028611428&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.7b00835

DO - 10.1021/acs.jmedchem.7b00835

M3 - Article

VL - 60

SP - 7146

EP - 7165

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 16

ER -